U.S. patent number 5,686,482 [Application Number 08/718,576] was granted by the patent office on 1997-11-11 for n-(3-pyrrolidinyl) benzamide derivative.
This patent grant is currently assigned to Yamanouchi Pharmaceutical Co., Ltd.. Invention is credited to Kazuyuki Hidaka, Kyoichi Maeno, Kazuhiro Nakato, Junya Ohmori, Shuichi Sakamoto, Shin-ichi Tsukamoto.
United States Patent |
5,686,482 |
Ohmori , et al. |
November 11, 1997 |
N-(3-pyrrolidinyl) benzamide derivative
Abstract
N-(3-Pyrrodinyl)benzamide derivatives represented by the
following general formula (I) which have potent and selective
antagonism against dopamine D.sub.3 and/or D.sub.4 receptor and are
useful as a psychotropic, a schizophrenia-treating agent and the
like, or a pharmaceutically acceptable salt thereof or a
pharmaceutical preparation thereof. ##STR1##
Inventors: |
Ohmori; Junya (Ibaraki,
JP), Maeno; Kyoichi (Ibaraki, JP), Hidaka;
Kazuyuki (Chiba, JP), Nakato; Kazuhiro (Ibaraki,
JP), Sakamoto; Shuichi (Ibaraki, JP),
Tsukamoto; Shin-ichi (Ibaraki, JP) |
Assignee: |
Yamanouchi Pharmaceutical Co.,
Ltd. (Tokyo, JP)
|
Family
ID: |
14011926 |
Appl.
No.: |
08/718,576 |
Filed: |
October 2, 1996 |
PCT
Filed: |
April 26, 1995 |
PCT No.: |
PCT/JP95/00818 |
371
Date: |
October 02, 1996 |
102(e)
Date: |
October 02, 1996 |
PCT
Pub. No.: |
WO95/29891 |
PCT
Pub. Date: |
November 09, 1995 |
Foreign Application Priority Data
|
|
|
|
|
Apr 28, 1994 [JP] |
|
|
6-090922 |
|
Current U.S.
Class: |
514/426; 548/529;
548/557 |
Current CPC
Class: |
C07D
207/14 (20130101) |
Current International
Class: |
C07D
207/00 (20060101); C07D 207/14 (20060101); C07D
207/06 (); A61K 031/40 () |
Field of
Search: |
;548/529,557
;514/426 |
References Cited
[Referenced By]
U.S. Patent Documents
|
|
|
3966957 |
June 1976 |
Cale, Jr. et al. |
4109005 |
August 1978 |
Lunsford et al. |
|
Primary Examiner: McKane; Joseph
Attorney, Agent or Firm: Sughrue, Mion, Zinn, Macpeak &
Seas, PLLC
Claims
We claim:
1. A novel N-(3-pyrrolidinyl)benzamide compound represented by a
general formula (I), or a pharmaceutically acceptable salt thereof,
##STR120## wherein each symbol in the formula has the following
meaning, R.sup.1 : a hydrogen atom, a lower alkyl group, an aralkyl
group or a cycloalkyl or cycloalkyl-lower alkyl group having 3 to 8
ring atoms,
R.sup.2 : a bicyclic or tricyclic bridged hydrocarbon ring group
having 4 to 16 ring atoms, which may be substituted by a lower
alkyl group(s),
R.sup.3 : a lower alkoxy group, an amino group or a mono- or
di-lower alkylamino group,
R.sup.4 : a hydrogen atom, a halogen atom, a lower alkyl group
which may be substituted by a hydroxyl group, a lower alkoxy group,
a cyano group, a nitro group, an amino group, a mono- or di-lower
alkylamino group, an acyl group or a group represented by
--S(O).sub.m --R.sup.5,
R.sup.5 : a lower alkyl group, an amino group or a mono- or
di-lower alkylamino group,
m: 0, 1 or 2,
X: a bond or a group represented by --O--, --S(O).sub.n --,
--NH--or --CONH--, and
n: 0, 1 or 2,
with the proviso that, when R.sup.1 is a cycloalkyl group, the
cases wherein X is a group represented by --CONH--, R.sup.3 is a
lower alkoxy group and R.sup.4 is a halogen atom are excluded.
2. The compound according to claim 1, wherein the group R.sup.1 is
a lower alkyl group or a cycloalkyl or cycloalkyl-lower alkyl group
having 3 to 8 ring atoms, the group R.sup.3 is a lower alkoxy group
and the group R.sup.4 is a halogen atom, cyano group or nitro
group.
3. The compound according to claim 2, wherein the group R.sup.2 is
a bicyclononyl group or an adamantyl group.
4. The compound according to any one of claims 1 to 3, wherein it
is (i) an optical isomer, (ii) an endo-exo isomer and (iii) an
optical isomer and an endo-exo isomer.
5. N-[1-(Bicyclo[
3.3.1]non-9-yl)-3-pyrrolidinyl]-2,4-dimethoxy-5-nitrobenzamide or a
pharmaceutically acceptable salt thereof or an optical isomer
thereof.
6.
N-[1-(Bicyclo[3.3.1]non-9-yl)-3-pyrrolidinyl]-2-methoxy-4-methyl-5-n
itrobenzamide or a pharmaceutically acceptable salt thereof or an
optical isomer thereof.
7. N-[1-(Bicyclo
[3.3.1]non-9-yl)-3-pyrrolidinyl]-5-cyano-2,4-dimethoxybenzamide or
a pharmaceutically acceptable salt thereof or an optical isomer
thereof.
8.
N-[1-(Bicyclo[3.3.1]non-9-yl)-3-pyrrolidinyl]-2,4-dimethoxy-5-methyl
aminobenzamide or a pharmaceutically acceptable salt thereof or an
optical isomer thereof.
9. A pharmaceutical composition which comprises the
N-(3-pyrrolidinyl)benzamide compound of any one of claims 1 to 8 or
a pharmaceutically acceptable salt thereof or an isomer thereof and
a pharmaceutically acceptable carrier.
10. A dopamine D.sub.3 receptor antagonist, a D.sub.4 receptor
antagonist or a D.sub.3 and D.sub.4 receptor antagonist, which
comprises the N-(3-pyrrolidinyl)benzaminde derivative of any one of
claims 1 to 3 or a pharmaceutically acceptable salt thereof or an
isomer thereof as an active ingredient.
11. The dopamine D.sub.3 receptor antagonist, D.sub.4 receptor
antagonist or D.sub.3 and D.sub.4 receptor antagonist according to
claim 10, wherein it is a psychotropic agent.
12. The dopamine D.sub.3 receptor antagonist, D.sub.4 receptor
antagonist or D.sub.3 and D.sub.4 receptor antagonist according to
claim 10, wherein it is a schizophrenia-treating agent.
Description
This application is a 371 of PCT/JP95/00818 filed Apr. 26, 1995
published as WO95/29891 Nov. 9, 1995.
TECHNICAL FIELD
This invention relates to N-(3-pyrrolidinyl)benzamide derivatives,
or a pharmaceutically acceptable salt thereof, which have selective
and high affinity for dopamine D.sub.3 (to be referred to as
D.sub.3 hereinafter) receptor and/or dopamine D.sub.4 (to be
referred to as D.sub.4 hereinafter) receptor and weak action upon
dopamine D.sub.2 (to be referred to as D.sub.2 hereinafter)
receptor. It also relates to D.sub.3 receptor and/or D.sub.4
receptor antagonists which contain N-(3-pyrrolidinyl)benzamide
derivatives or a pharmaceutically acceptable salt thereof as their
active ingredient.
BACKGROUND ART
Dopamine, i.e., 4-(2-aminoethyl)-1,2-benzenediol, takes markedly
varied and important roles in the central nervous system and
peripheral nervous system. In the conventional studies, dopamine
receptor has been classified into D.sub.1 like receptor and D.sub.2
like receptor based on a pharmacological classification. The
D.sub.2 like receptor is deeply related to mental functions and
locomotive functions, and a number of drugs which act upon this
type of receptor are used mainly as psychotropic agents for use in
the treatment of schizophrenia, depression and other mental
diseases/ Typical examples of such drugs include haloperidol,
sulpiride and the like. However, though these drugs show excellent
effects upon symptoms which are called positive symptoms of
schizophrenia (e.g., psychomotor excitement, hallucination,
delusion and the like), their effects are not sufficient for the
patients of chronic schizomycosis mainly having negative symptoms
such as lack of spontaneity, disappearance of interest, flattening
of affect and the like. In addition, these drugs are accompanied by
adverse side effects, though the degree varies. Typical examples of
such side effects are so-called extrapyramidal symptoms in which
diskinetic disorders are mainly generated, such as dystonia,
Parkinson disease-like symptoms and akathisia which occur in a
relatively acute manner with a relatively high frequency, and
intractable tardive dyskinesia which is generated after prolonged
administration.
In addition to the above, endocrine symptoms such as
hyperprolactinemia, amenorrhea and the like are also developed.
It is considered in general that the psychotropic action, which is
the main action of these drugs, is based on an action mediated by
the D.sub.2 like receptor which is present in the frontal cortex
and limbic system, the extrapyramidal symptoms as side effects are
based on an action mediated by the D.sub.2 like receptor which is
present in the striate body and the endocrine symptom-based side
effects are based on an action mediated by the D.sub.2 like
receptor which is present in the anterior lobe of hypophysis
(Baldessarini, R. L., "Drugs and the treatment of psychiatric
disorders" in Gilman, A. G. et al., eds. "The Pharmacological Basis
of Therapeutics 8th Ed.", Pergamon Press, New York, 1990, pp.
383-435).
With the development of genetic engineering in recent years, new
dopamine receptor subtypes have been discovered, and the dopamine
receptor has been re-classified into five subtypes of D.sub.1 to
D.sub.5 receptors having different constituting amino acid
sequences. Thus, it was revealed that the D.sub.2 like receptor
based on the conventional pharmacological classification is a
subfamily which includes the D.sub.2 receptor and newly discovered
D.sub.3 receptor and D.sub.4 receptor, and the D.sub.1 like
receptor is a subfamily which includes the D.sub.1 receptor and
D.sub.5 receptor [David R. et al., Trends in Pharmacological
Science 13, 61-69 (1992)].
It is also known that the D.sub.2, D.sub.3 and D.sub.4 receptors
belonging to the D.sub.2 like receptor subfamily have
characteristic differences in terms of their intracerebral
distribution [Bouthenet M-L. et al., Brain Res., 564, 203-219
(1991), Gehlert D. et al., Eur. J. Pharmacol., 211, 189-194 (1992)
and Van Tol H. H. M. et al., Nature, 350, 610 (1991)]. The D.sub.2
receptor is distributed particularly frequently in the striate body
which relates to the onset of extrapyramidal symptoms as a main
side effect and also relatively frequently in the nucleus accumbens
and olfactory tuberculum or in the pituitary body which relates to
the onset of endocrine symptoms, but its distribution in the brain
cortex which relates to mental functions is relatively rare. On the
other hand, the D.sub.3 receptor is distributed most frequently in
the limbic system and also distributed in the nucleus accumbens,
olfactory tuberculum, hippocampus, medial papillary nucleus,
tegmentum ventral mesencephali which are considered to be related
to cognition function and emotion, and the 10th lobe of the
cerebellum, but is rare in the striate body and not detectable in
the pituitary body. The D.sub.4 receptor is frequently distributed
in the frontal cortex which are considered to have most deeper
relation with schizophrenia through the regulation of higher mental
function in human and amygdala, but its distribution in the striate
body is very small. As a case in which schizophrenia is related to
the D.sub.4 receptor [Taubes G., Science, 265, 1034 (1994)], it has
been reported that concentration of the D.sub.4 receptor in
schizophrenia patients was about 6 times higher than the case of
healthy persons [Seeman P. et al., Nature, 365, 441 (1993)].
On the other hand, actions of existing antipsychotic agent upon
D.sub.3 and/or D.sub.4 receptor have also been revealed, and it is
considered that pharmacological characteristics of each drug are
based on the difference in its efficacy and selectivity for
respective D.sub.2, D.sub.3 and D.sub.4 subtype receptors [Soholoff
P., Nature, 347, 146-151 (1990) and Lahti R. A., Eur. J. of
Pharmacology, 236, 483 (1993)]. That is, a drug having highly
frequent onset of side effects (e.g., extrapyramidal symptoms),
such as haloperidol, has high affinity for D.sub.2 receptor in
comparison with D.sub.3 receptor and/or D.sub.4 receptor. Also, in
the case of drug which is classified as an atypical antipsychotic
agent (e.g., sulpiride), has relatively small side effects such as
extrapyramidal symptoms and the like, and shows certain degree of
effects on negative symptoms, its affinity for D.sub.3 and/or
D.sub.4 receptor is similar to its affinity for D.sub.2 receptor.
In the case of clozapine which is classified as an atypical
antipsychotic agent, has small extrapyramidal symptoms and is
effective for patients mainly having negative symptoms which are
resistant against conventional antipsychotic agent, its affinity
for D.sub.4 receptor is higher than its affinity for D.sub.2
receptor (its affinity for D.sub.4 receptor is several times higher
than that for D.sub.2 receptor). As an example which suggests that
the anti-schizophrenic action of clozapine is based on its action
upon D.sub. receptor, it has been reported that effective blood
concentration in a clinical dose of clozapine coincided well with a
value derived from the D.sub.4 receptor affinity rather than from
the D.sub.2 receptor affinity [Arnt J., in "Dopamine Receptors vol.
8" Liss, New York, 1987, pp. 199-231, Kane J. et al., Arch. Gen.
Psychiat., 45, 789 (1988), Casey D. E., Psychopharmacology, 99, 547
(1989), Seeman P., Neuropsychopharmacology, 7, 261 (1992)].
These findings strongly suggest that psychotropic actions including
improvement of negative symptoms are developed via the D.sub.3
and/or D.sub.4 receptor, and side effects such as extrapyramidal
symptoms and the like are generated via the D.sub.2 receptor
[Taubes G., Science, 265, 1034 (1994)].
As is evident from the aforementioned findings, it is an important
subject from the clinical viewpoint to create a drug which is free
from side effects such as extrapyramidal symptoms, endocrine
symptoms and the like and has excellent psychotropic actions
including actions to improve negative symptoms of
schizophrenia.
On the other hand, compounds disclosed in an unexamined published
Japanese patent application (kokai) No. 53-139728, an unexamined
published Japanese patent application (kokai) No. 53-92763, an
unexamined published Japanese patent application (kokai) No.
54-138553, an unexamined published Japanese patent application
(kokai) No. 57-2266 and Journal of Medicinal Chemistry, 24, 1224
(1981) are known as N-(3-pyrrolidinyl)benzamide derivatives, but
the affinity for both D.sub.3 receptor and D.sub.4 receptor is not
suggested or disclosed.
In addition, though compounds having affinity for the D.sub.3
receptor are disclosed in EP-A-0539281 and WO 94/03426 pamphlet,
not only their structures are clearly different from that of the
compounds of the present invention but also their affinity for the
D.sub.4 receptor and D.sub.2 receptor is not disclosed
illustratively.
DISCLOSURE OF THE INVENTION
It is an object of the present invention to provide compounds which
have more potent and selective affinity for the D.sub.3 receptor
and/or D.sub.4 receptor in comparison with the affinity of
clozapine, thereby showing excellent central functions and/or
peripheral functions including actions to improve negative symptoms
of schizophrenia, and is free from or has remarkably reduced side
effects such as extrapyramidal symptoms, endocrine symptoms based
on its action upon the D.sub.2 receptor.
Another object of the present invention is to provide D.sub.3
receptor and/or D.sub.4 receptor antagonists which use compounds
represented by a general formula (I) that will be described later,
as their active ingredient.
The inventors of the present invention have created various
compounds and conducted screening works and, as a result, found
that novel compounds whose chemical structures are different from
those of prior art compounds in terms of a point that the
N-(3-pyrrolidinyl)benzamides have an pyrrolidin-3-yl group of which
1-position is substituted with a bicyclic or tricyclic bridged
hydrocarbon ring group.
Thereafter, the present invention was accomplished by revealing
that the N-(3-pyrrolidinyl)benzamide derivatives of the present
invention or a pharmaceutically acceptable salt thereof have high
selectivity and potent affinity for the D.sub.3 receptor and/or
D.sub.4 receptor and extremely weak action upon the D.sub.2
receptor and by predicting that the invention compound can exert
psychotropic actions against diseases such as schizophrenia,
emotional disorder, anxiety, sleep disorder, organic mental
disorder, drug abuse, personality disorder and the like, and
central and/or peripheral actions against diseases which are
accompanied by difficulty of moving (e.g., Parkinson disease), as
well as sexual disorder, pain, vomiting, hypertension, urination,
diarrhea, digestive organ indefinite complaint and the like, while
side effects such as extrapyramidal symptoms, endocrine symptoms
and the like are not generated or remarkably reduced, so that the
clinical object can be achieved. In consequence, it is possible to
apply the compounds of the present invention as therapeutic drugs
to patients who have difficulty in using drugs because of a
possible danger of causing side effects, for example senile and
child patients.
Accordingly, the present invention relates to a novel
N-(3-pyrrolidinyl)benzamide derivative represented by a general
formula (I), or a pharmaceutically acceptable salt thereof,
##STR2## wherein each symbol in the formula has the following
meaning, R.sup.1 : a hydrogen atom, a lower alkyl group, an aralkyl
group or a cycloalkyl or cycloalkyl-lower alkyl group having 3 to 8
ring atoms,
R.sup.2 : a bicyclic or tricyclic bridged hydrocarbon ring group
having 4 to 16 ring atoms, which may have a lower alkyl
group(s),
R.sup.3 : a lower alkoxy group, an amino group or a mono- or
di-lower alkylamino group,
R.sup.4 : a hydrogen atom, a halogen atom, a lower alkyl group
which may have a hydroxyl group, a lower alkoxy group, a cyano
group, a nitro group, an amino group, a mono- or di-lower
alkylamino group, an acyl group or a group represented by
--S(O).sub.m --R.sup.5,
R.sup.5 : a lower alkyl group, an amino group or a mono- or
di-lower alkylamino group,
m: 0, 1 or 2,
X: a bond or a group represented by --O--, --S(O).sub.n --,
--NH--or --CONH--, and
n: 0, 1 or 2,
with the proviso that, when R.sup.1 is a cycloalkyl group, the
cases wherein X is a group represented by --CONH--, R.sup.3 is a
lower alkoxy group and R.sup.4 is a halogen atom are excluded.
Particularly preferred among the compounds of the present invention
is a compound or a pharmaceutically acceptable salt thereof in
which the group R.sup.1 is a lower alkyl group or a cycloalkyl or
cycloalkyl-lower alkyl group having 3 to 8 ring atoms, the group
R.sup.3 is a lower alkoxy group and the group R.sup.4 is a halogen
atom, a cyano group or a nitro group.
Further preferred compound of the present invention is compounds or
a pharmaceutically acceptable salt thereof in which the group
R.sup.2 is bicyclononyl group or adamantyl group.
The present invention also relates to a pharmaceutical composition
which comprises N-(3-pyrrolidinyl)benzamide derivatives represented
by the aforementioned general formula (I) or a pharmaceutically
acceptable salt thereof and a pharmaceutically acceptable carrier,
as well as D.sub.3 and/or D.sub.4 receptor antagonists which
comprise said N-(3-pyrrolidinyl)benzamide derivatives or a
pharmaceutically acceptable salt thereof as an active
ingredient.
Preferably, the just described pharmaceutical compositions or
antagonists are pharmaceutical compositions which comprise
compounds or a pharmaceutically acceptable salt thereof wherein, in
the aforementioned general formula (I), the group R.sup.1 is a
lower alkyl group or a cycloalkyl or cycloalkyl-lower alkyl group
having 3 to 8 ring atoms, the group R.sup.3 is a lower alkoxy group
and the group R.sup.4 is a halogen atom, a cyano group or a nitro
group, or D.sub.3 and/or D.sub.4 receptor antagonists which contain
the same as an active ingredient.
More preferred pharmaceutical compositions or antagonists are a
pharmaceutical composition which comprise compounds or a
pharmaceutically acceptable salt thereof wherein the group R.sup.2
is a bicyclononyl group or an adamantyl group, or D.sub.3 and/or
D.sub.4 receptor antagonists which contain the same as an active
ingredient.
The following describes the compound of the present invention in
detail.
The term "lower" as used herein means a straight or branched carbon
chain having 1 to 6 carbon atoms.
In consequence, examples of the "lower alkyl group" include methyl,
ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,
pentyl (amyl), isopentyl, neopentyl, tert-pentyl, 1-methylbutyl,
2-methylbutyl, 1,2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl,
2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl,
1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl,
2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl,
1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl,
1-ethyl-2-methylpropyl and the like.
Of these groups, C.sub.1 -C.sub.4 alkyl groups, particularly
C.sub.1 -C.sub.3 alkyl groups are preferred.
Examples of the "lower alkoxy group" include methoxy, ethoxy,
propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy,
pentyloxy (amyloxy), isopentyloxy, tert-pentyloxy, neopentyloxy,
2-methylbutoxy, 1,2-dimethylpropoxy, 1-ethylpropoxy, hexyloxy and
the like, of which methoxy group is particularly preferred.
Examples of the "halogen atom" include a fluorine atom, a chlorine
atom, a bromine atom, an iodine atom and the like, of which
chlorine and bromine atoms are particularly preferred.
The "cycloalkyl group" is those having 3 to 8 carbon atoms, and its
illustrative examples include cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl and cyclooctyl.
The term "cycloalkyl-lower alkyl group" means a group in which the
aforementioned "lower alkyl group" is substituted with the
aforementioned "cycloalkyl group".
The term "aralkyl group" means a group in which an optional
hydrogen atom of the aforementioned "lower alkyl group" is
substituted with an "aryl group" such as phenyl, naphthyl or the
like. When phenyl or naphthyl is employed as the example of the
aryl group, its illustrative examples include benzyl, phenetyl,
1-phenylethyl, 3-phenylpropyl, 2-phenylpropyl, 1-phenylpropyl,
1-methyl-2-phenylethyl, 4-phenylbutyl, 3-phenylbutyl,
2-phenylbutyl, 1-phenylbutyl, 2-methyl-3-phenylpropyl,
2-methyl-2-phenylpropyl, 2-methyl-1-phenylpropyl,
1-methyl-3-phenylpropyl, 1-methyl-2-phenylpropyl,
1-methyl-1-phenylpropyl, 1-ethyl-2-phenylethyl,
1,1-dimethyl-2-phenylethyl, 5-phenylpentyl, 4-phenylpentyl,
3-phenylpentyl, 2-phenylpentyl, 1-phenylpentyl,
3-methyl-4-phenylbutyl, 3-methyl-3-phenylbutyl,
3-methyl-2-phenylbutyl, 3-methyl-1-phenylbutyl, 6-phenylhexyl,
5-phenylhexyl, 4-phenylhexyl, 3-phenylhexyl, 2-phenylhexyl,
1-phenylhexyl, 4-methyl-5-phenylpentyl, 4-methyl-4-phenylpentyl,
4-methyl-3-phenylpentyl, 4-methyl-2-phenylpentyl,
4-methyl-1-phenylpentyl, 1-naphthylmethyl, 2-naphthylmethyl,
2-(1-naphthyl)ethyl, 2-(2-naphthyl)ethyl, 1-(1-naphthyl)ethyl,
1-(2-naphthyl)ethyl, 3-(1-naphthyl)propyl, 3-(2-naphthyl)propyl,
2-(1-naphthyl)propyl, 2-(2-naphthyl)propyl, 1-(1-naphthyl)propyl,
1-(2-naphthyl)propyl, 1-methyl-2-(1-naphthyl)ethyl,
1-methyl-2-(2-naphthyl)ethyl, 4-(1-naphthyl)butyl,
4-(2-naphthyl)butyl, 3-(1-naphthyl)butyl, 3-(2-naphthyl)butyl,
2-(1-naphthyl)butyl, 2-(2-naphthyl)butyl, 1-(1-naphthyl)butyl,
1-(2-naphthyl)butyl, 2-methyl-3-(1-naphthyl)propyl,
2-methyl-3-(2-naphthyl)propyl, 2-methyl-2-(1-naphthyl)propyl,
2-methyl-2-(2-naphthyl)propyl, 2-methyl-1-(1-naphthyl)propyl,
2-methyl-1-(2-naphthyl)propyl, 5-(1-naphthyl)pentyl,
5-(2-naphthyl)pentyl, 4-(1-naphthyl)pentyl, 4-(2-naphthyl)pentyl,
3-methyl-4-(1-naphthyl)butyl, 3-methyl-4-(2-naphthyl)butyl,
6-(1-naphthyl)hexyl, 6-(2-naphthyl)hexyl, 5-(1-naphthyl)hexyl,
5-(2-naphthyl)hexyl, 4-methyl-5-(1-naphthyl)pentyl,
4-methyl-5-(2-naphthyl)pentyl, diphenylmethyl (benzhydryl),
triphenylmethyl (trityl) and the like.
With regard to the "bicyclic or tricyclic bridged hydrocarbon ring
group having 4 to 16 ring atoms, which may have a lower alkyl
group(s)", a saturated or unsaturated bicyclic or tricyclic bridged
hydrocarbon ring group consisting of 2 or 3 cycloalkyl rings of 3
to 8 carbon atoms is preferred, and its illustrative examples
include bicyclo[2.1.1]hexyl, bicyclo[3.1.1]heptyl,
bicyclo[2.2.2]octyl, bicyclo[4.3.1]decyl, bicyclo[3.3.1]nonyl,
bornyl, bornenyl, norbornyl, norbornenyl,
6,6-dimethylbicyclo[3.1.1]heptyl, tricyclobutyl, adamantyl,
noradamantyl (tricyclo[3.3.1.0..sup.3.7 ]nonyl),
tricyclo[7.3.2.0..sup.5.13 ]tetradecyl and the like. Of these
groups, bicyclo[3.3.1]nonyl and adamantyl are preferred.
The term "mono- or di-lower alkylamino group" as used herein means
a group in which 1 or 2 hydrogen atoms of an amino group is
substituted with the aforementioned "lower alkyl group". The
illustrative examples include monoalkylamino groups substituted
with a straight or branched alkyl group having 1 to 6 carbon atoms,
such as methylamino, ethylamino, propylamino, isopropylamino,
butylamino, isobutylamino, pentylamino, isopentylamino, hexylamino,
isohexylamino and the like, symmetric dialkylamino groups
di-substituted with a straight or branched alkyl group having 1 to
6 carbon atoms, such as dimethylamino, diethylamino, dipropylamino,
diisopropylamino, dibutylamino, dipentylamino, dihexylamino and the
like, and asymmetric dialkylamino groups di-substituted with alkyl
groups which are different from each other and selected from
straight or branched alkyl groups each having 1 to 6 carbon atoms,
such as ethylmethylamino, methylpropylamino, ethylpropylamino,
butylmethylamino, butylethylamino, butylpropylamino and the
like.
Examples of the "acyl group" include lower alkanoyl groups and
arylcarbonyl group, and examples of the lower alkanoyl group
include formyl, acetyl, propionyl, butylyl, isobutylyl, valeryl,
isovaleryl, pivaloyl, hexanoyl and the like and examples of the
arylcarbonyl group include benzoyl, naphthoyl and the like.
Some members of the compound (I) of the present invention may form
acid addition salts. Pharmaceutically acceptable salts of the
compound (I) are included in the present invention, and examples of
such salts include acid addition salts with inorganic acids such as
hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric
acid, nitric acid, phosphoric acid and the like or with organic
acids such as formic acid, acetic acid, propionic acid, oxalic
acid, malonic acid, succinic acid, fumaric acid, maleic acid,
lactic acid, malic acid, citric acid, tartaric acid, carbonic acid,
picric acid, methanesulfonic acid, ethanesulfonic acid,
toluenesulfonic acid, glutamic acid, aspartic acid and the
like.
Also, since the compound of the present invention contains
asymmetric carbon atoms, it exists in the form of optical isomers
(optical antipode, racemic modification, diastereomer) based
thereon. The compound of the present invention also exists in the
form of endo-exo isomers based on the presence of bridged rings.
All of these isomers as mixtures or isolated forms are included in
the present invention.
In addition, the compound of the present invention is sometimes
isolated as a hydrate, various types of solvates or a polymorphic
substance, and these substances are also included in the present
invention.
The following compounds are particularly preferred examples of the
compound of the present invention. 1.
N-[1-(Bicyclo[3.3.1]non-9-yl)-3-pyrrolidinyl]-2,4-dimethoxy-5-nitrobenzami
de or pharmaceutically acceptable salts thereof or optical isomers
thereof. 2.
N-[1-(Bicyclo[3.3.1]non-9-yl)-3-pyrrolidinyl]-2-methoxy-4-methyl-5-nitrobe
nzamide or pharmaceutically acceptable salts thereof or optical
isomers thereof. 3.
N-[1-(Bicyclo[3.3.1]non-9-yl)-3-pyrrolidinyl]-5-cyano-2,4-dimethoxybenzami
de or pharmaceutically acceptable salts thereof or optical isomers
thereof. 4.
N-[1-(Bicyclo[3.3.1]non-9-yl)-3-pyrrolidinyl]-2,4-dimethoxy-5-methylaminob
enzamide or pharmaceutically acceptable salts thereof or optical
isomers thereof.
(Production Methods)
The compounds of the present invention can be produced by employing
various synthetic methods. The following describes typical
production methods.
Examples of suitable inert solvents to be used in the following
description include methylene chloride, chloroform, dichloroethane,
benzene, toluene, ether, hexane, tetrahydrofuran, dioxane,
dimethylformamide, acetonitrile, dimethyl sulfoxide and the
like.
Examples of suitable condensing agents include carbodiimide
derivatives typically including N,N'-dicyclohexylcarbodiimide (as
occasion demands, the reaction may be carried out by adding an
additive agent such as 1-hydroxybenzotriazole, N-hydroxysuccinimide
or the like), water soluble carbodiimides typically including
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride,
diphenylphosphoryl azide, azo derivatives typically including
diethyl azodicarboxylate, with triphenylphosphine,
N,N'-carbonyldiimidazole,
benzotriazol-1-yloxytris(dimethylamino)phosphonium
hexafluorophosphate and the like.
Examples of suitable inorganic bases include sodium hydride, sodium
hydroxide, sodium bicarbonate, sodium carbonate, potassium
hydroxide, potassium carbonate and the like and examples of
suitable organic bases include pyridine, triethylamine,
diisopropylethylamine, N,N'-dimethylaminopyridine,
1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane,
butyl lithium, lithium bis(trimethylsilyl)amide and the like.
Suitable mineral acid includes hydrochloric acid, sulfuric acid and
the like, suitable organic acid includes acetic acid,
toluenesulfonic acid and the like and suitable Lewis acid includes
aluminum chloride, titanium tetrachloride, orthotitanic acid
isopropoxide and the like.
Examples of suitable catalyst include palladium, platinum and
rhenium, each in powder form or being supported on a carrier, as
well as Raney nickel and the like.
Examples of suitable metal hydride complex include sodium
borohydride, sodium cyanoborohydride, sodium trimethoxyborohydride
and the like.
Method 1
In this method, the N-(3-pyrrolidinyl)benzamide derivative (I) is
produced by carrying out condensation reaction of a benzoic acid
derivative represented by the following formula (II) or (III) with
a 3-aminopyrrolidine derivative (IV).
Part 1) Condensation reaction of benzoic acid derivative (II) with
3-aminopyrrolidine derivative
This reaction is effected according to the condensation of a
carboxylic acid with an amine. In general, this reaction is carried
out with cooling, at room temperature or with heating in the
presence or absence of a suitable inert solvent and, if necessary,
in the presence of a suitable condensation agent. ##STR3## (In the
above formulae, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and X are as
defined in the foregoing.)
Part 2) Reaction of 3-aminopyrrolidine derivative (IV) with a
benzoyl halide, benzoyl azide, benzoic ester or benzoic anhydride
represented by general formula (III)
This reaction is effected by the condensation of an amine with a
reactive derivative of carboxylic acid, such as an acyl halide
(e.g., a chloride, bromide or iodide), an acyl azide, an active
ester or an acid anhydride. In general, this reaction is carried
out under cooling, at room temperature or with heating in the
presence or absence of a suitable inert solvent and, if necessary,
by adding a suitable inorganic or organic base or by using a
suitable organic base as both a solvent and an acid acceptor.
##STR4## Method 2
In this method, the N-(3-pyrrolidinyl)benzamide derivative (I) is
produced by introducing a substituent group to the nitrogen atom on
the pyrrolidine nucleus of an N-(3-pyrrolidinyl)benzamide
derivative (V).
Part 1) A production method by reductive alkylation reaction of
N-(3-pyrrolidinyl)benzamide derivative (V) with an aldehyde or
ketone represented by general formula (VI) corresponding to R.sup.2
in the formula
This reaction is effected by reductive alkylation of an amine. For
example, this reaction may be carried out by stirring the
N-(3-pyrrolidinyl)benzamide derivative (V) and an aldehyde or
ketone represented by the general formula (VI) which corresponds to
R.sup.2 in the formula, in a suitable solvent (e.g., water,
methanol, ethanol, ethyl acetate, methylene chloride, chloroform,
dimethylformamide or acetic acid) in the presence of a suitable
catalyst at room temperature or with heating under atmospheric
hydrogen. As occasion demands, a suitable mineral acid, organic
acid or Lewis acid may be added to the reaction system, or the
reaction system may be pressurized. Alternatively, the reaction may
be effected by a reaction with a suitable metal hydride complex in
a suitable solvent (for example, methanol, ethanol,
tetrahydrofuran, dioxane, benzene, toluene, hexane or
dimethylformamide) under cooling, at room temperature or with
heating. As occasion demands, a suitable mineral acid, organic acid
or Lewis acid may be added to the reaction system. ##STR5## (In the
above formulae, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and X are as
defined in the foregoing.)
Part 2) Reaction of N-(3-pyrrolidinyl)benzamide derivative (V) with
a halide or sulfonate represented by general formula (VII)
This reaction may be carried out by allowing the
N-(3-pyrrolidinyl)benzamide derivative (V) to react with a halide
(e.g., chloride, bromide or iodide) or a sulfonate (e.g., p-toluene
sulfonate, trifluoromethane sulfonate) represented by the general
formula (VII) in the presence or absence of a suitable inert
solvent under cooling, at room temperature or with heating and, if
necessary, by adding a suitable inorganic or organic base as an
acid acceptor or by using a suitable organic base as both a solvent
and an acid acceptor. ##STR6## (In the above formulae, R.sup.1,
R.sup.2, R.sup.3, R.sup.4 and X are as defined in the foregoing and
Z means a halogen atom or an organic sulfonic acid residue.)
Method 3
In this method, the N-(3-pyrrolidinyl)benzamide derivative (I) is
produced by constructing a pyrrolidine ring through cyclization
condensation of an N-substituted benzamide derivative represented
by a general formula (VIII), (IX), (X) or (XI).
Part 1) Intramolecular reductive alkylation of N-substituted
benzamide derivative (VIII) or (IX)
This reaction is effected by conventional reductive alkylation of
amine. For example, the reaction may be effected by stirring the
compound (VIII) or (IX) in a suitable solvent (e.g., methanol,
ethanol, ethyl acetate, dimethylformamide, acetic acid, methylene
chloride or chloroform) in the presence of a suitable catalyst at
room temperature, with cooling or with heating under atmospheric
hydrogen. As occasion demands, a suitable mineral acid, organic
acid or Lewis acid may be added to the reaction system or the
reaction system may be pressurized.
Alternatively, the reaction may be effected by a reaction with a
suitable metal hydride complex in a suitable solvent (e.g.,
methanol, ethanol, tetrahydrofuran, dioxane, benzene, toluene,
hexane or dimethylformamide) under cooling, at room temperature or
with heating. As occasion demands, a suitable mineral acid, organic
acid or Lewis acid may be added to the reaction system. ##STR7##
(In the above formulae, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and X
are as defined in the foregoing.)
Part 2) Intramolecular N-alkylation of N-substituted benzamide
derivative (X) or (XI)
This reaction may be effected by carrying out intramolecular
cyclization of an N-substituted benzamide derivative (X) or (XI) in
the presence or absence of a suitable inert solvent under cooling,
at room temperature or with heating and, if necessary, by adding a
suitable inorganic or organic base as a deoxidizing agent or by
using a suitable organic base as both a solvent and an acid
acceptor. ##STR8## (In the above formulae, R.sup.1, R.sup.2,
R.sup.3, R.sup.4, X and Z are as defined in the foregoing.)
Method 4
In this method, the N-(3-pyrrolidinyl)benzamide derivative (I) is
produced by oxidizing, reducing, adding, substituting or
hydrolyzing the substituent group A or B of an N-substituted
benzamide derivative represented by a general formula (XII) or
(XIII). ##STR9## (In the above formulae, R.sup.1, R.sup.2, R.sup.3,
R.sup.4 and X are as defined in the foregoing, and A or B
independently represents a hydrogen atom, a halogen atom, an amino
group, an alkylamino group, an acylamino group, a nitro group, a
diazonium group, a hydroxyl group, a tosyloxy group, a
trifluoromethanesulfonyl group, a mesyl group, an acyl group, a
cyano group, an alkyl group, an alkenyl group, an alkynyl group, a
formyl group, a carboxyl group, a thiol group, an alkylthio group,
an alkylsulfonyl group, an alkylsulfoxyl group or a
halogenosulfonyl group.)
In this connection, some novel substances are included in the
starting compounds to be used in the aforementioned first to fourth
production methods, and such substances can be produced by using
corresponding known compounds as respective starting materials and
by employing techniques such as amidation, reductive N-alkylation,
N-alkylation, intramolecular reductive N-alkylation, intramolecular
N-alkylation, oxidation, reduction, addition, substitution,
hydrolysis and the like described in the Methods 1-4. Practical
production of these substances may be effected in accordance with
the Reference Examples which will be described later, or in
accordance with the respective procedures described in the
Reference Examples or by modifying them.
For example, the 3-aminopyrrolidine derivative represented by the
general formula (IV) can be produced by allowing 3-protected
aminopyrrolidine to react with a carbonyl, halogen or sulfonate
compound represented by R.sup.2 .dbd.O or R.sup.2 .dbd.Z in the
same manner as the case of the Method 2. Also, the starting
compound (II) can be produced by applying techniques of the Methods
2-4, such as hydrolysis and nitration of corresponding ester,
amination by reduction of nitro group, etherification or
thioetherification of a halide or a compound having hydroxyl group
or mercapto group, reductive N-alkylation or N-alkylation of a
compound having amino group, oxidation of a thioether compound,
conversion from amino group into halide and conversion from amino
group into nitrile.
The compounds (I) of the present invention produced by these
methods are isolated and purified in its free form or as a salt
thereof. Isolation and purification can be effected by using usual
chemical methods such as extraction, evaporation, crystallization,
filtration, recrystallization, various types of chromatography and
the like.
The thus obtained free compound or a salt thereof can be made into
another salt by subjecting it to commonly used salt forming
reaction.
In this connection, the compounds of the present invention contain
optical isomers, because it has at least 1 asymmetric carbon
atom.
These optical isomers can be separated in the usual way, for
example, by carrying out a fractional crystallization in which each
isomer is recrystallized with an appropriate salt or by a column
chromatography. Alternatively, a desired optical isomer can be
obtained from an appropriate optically active starting
material.
The following illustrates compounds other than those which will be
described in Examples, that can be synthesized in accordance with
the aforementioned production methods, particularly the methods
described in the Examples, or modified methods thereof known to
those skilled in the art.
TABLE 1
__________________________________________________________________________
##STR10## Compound No. R.sup.1 X R.sup.2 R.sup.3 R.sup.4
__________________________________________________________________________
1 H NH ##STR11## MeO O.sub.2 N 2 H NH ##STR12## MeO NC 3 H NH
##STR13## MeO NC 4 Me NH ##STR14## MeO O.sub.2 N 5 Et NH ##STR15##
MeO O.sub.2 N 6 .sup.1 Pr NH ##STR16## MeO O.sub.2 N 7 .sup.c Pr NH
##STR17## MeO O.sub.2 N 8 .sup.c PrCH.sub.2 - NH ##STR18## MeO
O.sub.2 N 9 Me NH ##STR19## MeO O.sub.2 N 10 .sup.n Pr NH ##STR20##
MeO O.sub.2 N 11 .sup.c Pr NH ##STR21## MeO O.sub.2 N 12 .sup.c
PrCH.sub.2 NH ##STR22## MeO O.sub.2 N 13 Me CONH ##STR23## MeO
O.sub.2 N 14 Me CONH ##STR24## MeO O.sub.2 N 15 .sup.c Pr CONH
##STR25## MeO O.sub.2 N 16 .sup.c Bu CONH ##STR26## MeO O.sub.2 N
17 .sup.c Bu CONH ##STR27## MeO O.sub.2 N 18 Me Bond ##STR28## MeO
NC 19 Me Bond ##STR29## MeO O.sub.2 N 20 Me Bond ##STR30## MeO Cl
21 Me Bond ##STR31## MeO NC 22 Me Bond ##STR32## MeO Cl 23 Et Bond
##STR33## MeO O.sub.2 N 24 .sup.n Pr Bond ##STR34## MeO O.sub.2 N
25 .sup.n Bu Bond ##STR35## MeO O.sub.2 N 26 EtMeCH Bond ##STR36##
MeO O.sub.2 N 27 Me Bond ##STR37## MeO O.sub.2 N 28 Et Bond
##STR38## MeO O.sub.2 N 29 .sup.n Pr Bond ##STR39## MeO O.sub.2 N
30 .sup.n Bu Bond ##STR40## MeO O.sub.2 N 31 EtMeCH Bond ##STR41##
MeO O.sub.2 N 32 .sup.c Hex Bond ##STR42## MeO O.sub.2 N 33 .sup.c
Hex Bond ##STR43## MeO O.sub.2 N 34 H NH ##STR44## MeO Cl 35 H NH
##STR45## EtO O.sub.2 N 36 H NH ##STR46## .sup.n PrO O.sub.2 N 37 H
NH ##STR47## .sup.1 PrO O.sub.2 N 38 Me O ##STR48## MeO MeNH 39
.sup.n Pr O ##STR49## MeO MeNH 40 .sup.c PrCH.sub.2 O ##STR50## MeO
MeNH 41 .sup.n Pr O ##STR51## MeO MeNH 42 .sup.c PrCH.sub.2 O
##STR52## MeO MeNH 43 .sup.c Hex O ##STR53## MeO MeNH 44 Me O
##STR54## MeO EtNH 45 Me O ##STR55## MeO EtNH 46 Me O ##STR56## MeO
.sup.1 PrNH 47 Me O ##STR57## MeO .sup.1 PrNH 48 Me O ##STR58## MeO
Me.sub.2 N 49 .sup.n Pr O ##STR59## MeO EtNH 50 .sup.n Pr O
##STR60## MeO .sup.1 PrNH 51 .sup.n Pr O ##STR61## MeO Me.sub.2 N
52 .sup.c PrCH.sub.2 O ##STR62## MeO EtNH 53 .sup.c PrCH.sub.2 O
##STR63## MeO .sup.1 PrNH 54 .sup.c PrCH.sub.2 O ##STR64## MeO
Me.sub.2 N 55 .sup.n Pr O ##STR65## MeO EtNH 56 .sup.n Pr O
##STR66## MeO .sup.1 PrNH 57 .sup.n Pr O ##STR67## MeO Me.sub.2 N
58 .sup.c PrCH.sub.2 O ##STR68## MeO EtNH 59 .sup.c PrCH.sub.2 O
##STR69## MeO .sup.1 PrNH 60 .sup.c PrCH.sub.2 O ##STR70## MeO
Me.sub.2 N
__________________________________________________________________________
In the above table, Me means methyl group, Et means ethyl group,
.sup.n Pr means normal propyl group, .sup.i Pr means isopropyl
group, .sup.n Bu means normal butyl group, .sup.c Pr means
cyclopropyl group, .sup.n Bu means cyclobutyl group and .sup.c Hex
means cyclohexyl group.
Industrial Applicability
Since the compound of the present invention has high affinity for
the D.sub.3 and/or D.sub.4 receptor and low affinity for the
D.sub.2 receptor, it is useful as psychotropic having reduced or no
side effects in relation to extrapyramidal symptoms and endocrine
systems, particularly as drugs for the treatment of schizophrenia,
feeling disorders, anxiety, psychomotor function disorders due to
drug abuse, psychiatric disorders in child and puberty stages and
problematic behavior of the aged, and as an analgesic or as drugs
for use in the central dopamine nervous system-related diseases,
such as an anti-Parkinson drug, an antiemetic and a
feeding-controlling drug. It is also useful as a hypotensive drug
or a diuretic, through a function mediated by a peripheral D.sub.3
receptor (Sokoloff P., Nature, 347, 146-151 (1990)).
Affinity of the compound of the present invention for D.sub.2
receptor, D.sub.3 receptor and D.sub.4 receptor was confirmed by
the following test methods.
1) Affinity for D.sub.2 receptor, D.sub.3 receptor and D.sub.4
receptor
Each of the D.sub.2 receptor, D.sub.3 receptor and D.sub.4 receptor
was subjected to gene cloning and the thus cloned gene was
introduced into host cells, thereby preparing cell strains capable
of expressing respective receptors (Sokoloff P. et al., Nature,
347, 146 (1990), Van Tol H. H. M. et al., Nature, 350, 610 (1994)).
Using membrane samples of these cells, affinity of compounds for
D.sub.2 receptor, D.sub.3 receptor and D.sub.4 receptor was
examined by a receptor binding test. The receptor binding test was
carried out in the following manner. A D.sub.2 receptor, D.sub.3
receptor or D.sub.4 receptor membrane sample and [.sup.125 I]
iodosulpride or [.sup.3 H] YM-09151-2 (trade name, manufactured by
Daiichi Pure Chemicals) were incubated at 25.degree. C. for 1 hour
in the presence of each compound to be tested. The reaction
solution was filtered through a glass filter to measure the amount
of radioisotope on the filter. Concentration of each test compound
which inhibits 50% of the receptor specific binding was used as
IC.sub.50 value, and the value was converted into Ki value based on
the formula of Cheng and Prusoff relationship [Cheng Y. et al.,
Biochem. Pharmacol., 22, 3099-3108, (1973)]. The results are shown
in Table 2.
TABLE 2 ______________________________________ Binding test (Ki
value, nM) Ratio Compound D.sub.2 D.sub.3 D.sub.4 D.sub.2 /D.sub.3
D.sub.2 /D.sub.4 ______________________________________ Clozapine
260 230 51 1.1 5.1 (Control compound) Example 7 72 1.5 1.1 48 65
Example 19 350 4.0 2.6 88 135 Example 30 34 3.5 1.8 9.7 19
______________________________________
In this receptor binding test, the compounds of the present
invention showed high affinity for D.sub.3 receptor and/or D.sub.4
receptor and excellent D.sub.3 receptor and/or D.sub.4 receptor
selectivity against D.sub.2 receptor in comparison with a known
antipsychotic agent (clozapine).
On the other hand, other typically known dopamine receptor blocking
agent showed affinity for D.sub.2, D.sub.3 and D.sub.4 receptors at
various ratios, but none of them showed selective affinity for
D.sub.3 and/or D.sub.4 receptor.
2) Antagonism test on apomorphine-induced climbing behavior
In order to evaluate antipsychotic action of the compound of the
present invention, antagonism of the compound of the present
invention and clozapine against apomorphine-induced climbing
behavior was measured. Each test compound was administered to ICR
mice (body weight, around 35 g; Japan SLC) by subcutaneous
injection and, after 15 minutes, apomorphine (2 mg/kg) was
subcutaneously injected. After 10 minutes of the final injection,
climbing behavior of the mice was measured during 30 minutes to
calculate ED.sub.50 value.
As a result, the compound of the present invention showed potent
antagonism against apomorphine-induced climbing behavior (Table
3).
TABLE 3 ______________________________________ Compound ED.sub.50
(mg/kg, SC adininistration) ______________________________________
Clozapine 6.8 (Control compound) Example 30 1.8
______________________________________
In consequence, usefulness of the compound of the present invention
as an antipsychotic agent can be expected.
When the compound represented by the general formula (I), a
non-toxic salt thereof, a stereoisomer thereof or a hydrate or
solvate thereof is used for the above purpose, it may be
administered orally or parenterally.
The dose may vary depending on the age, body weight, symptoms,
therapeutic effect, administration method, treating period and the
like, but, in general, it may be administered orally within a range
of from 0.1 mg to 100 mg, preferably from 1 mg to 50 mg, per day
per adult, by dividing the daily dose into one to several doses per
day, or parenterally within a range of from 0.1 mg to 100 mg per
day per adult, by dividing the daily dose into one to several doses
per day or by continuously administering the daily dose by
intravenous injection for 1 to 24 hours a day. Since the dose
varies depending on various conditions, a dose smaller than the
above range may be enough in some cases.
Tablets, powders, granules and the like may be used as the solid
composition for oral administration use of the present invention.
In such a solid composition, one or more active substances are
mixed with at least one inert diluent such as lactose, mannitol,
glucose, hydroxypropylcellulose, microcrystalline cellulose,
starch, polyvinyl pyrrolidone, magnesium metasilicate aluminate or
the like. In accordance with the conventionally used method, the
composition may contain additive agents other than the inert
diluent, such as lubricating agents (e.g., magnesium stearate),
disintegrating agents (e.g., calcium cellulose glycolate),
stabilizing agents (e.g., galactose), and solubilizing aids (e.g.,
glutamic acid, aspartic acid). As occasion demands, tablets or
pills may be coated with gastric or enteric coating films such as
of sucrose, gelatin, hydroxypropylcellulose,
hydroxypropylmethylcellulose phthalate and the like.
Examples of liquid composition for use in oral administration
include pharmaceutically acceptable emulsions, solutions,
suspensions, syrups, elixirs and the like which contain a generally
used inert diluent such as purified water, ethanol or the like. In
addition to the inert diluent, this composition may also contain
auxiliary agents such as a moistening agent and a suspending agent,
as well as a sweetening agent, a flavoring agent, an aroma, an
antiseptic agent and the like.
Injections for use in parenteral administration include aseptic
aqueous or non-aqueous solutions, suspensions and emulsions.
Examples of the aqueous solutions and suspensions include distilled
water for injection use and physiological saline. Examples of the
non-aqueous solutions and suspensions include propylene glycol,
polyethylene glycol, plant oil such as olive oil, alcohol such as
ethanol, Polysorbate 80 (trade name, a nonionic surface active
agent, polyoxyethylene sorbitan alkyl ester) and the like. Such a
composition may also contain auxiliary agents such as an antiseptic
agent, a moistening agent, an emulsifying agent, a dispersing
agent, a stabilizing agent (e.g., lactose), a solubilizing aid
(e.g., glutamic acid or aspartic acid) and the like. Sterilization
of these compositions may be effected by passing them through a
bacterial filter, formulating a germicide or light irradiation.
Alternatively, a corresponding aseptic solid composition may be
produced which is used by dissolving in aseptic water or an aseptic
solvent for injection use prior to its use.
BEST MODE OF CARRYING OUT THE INVENTION
Examples of the present invention are given below by way of
illustration and not by way of limitation. First, examples of the
production of starting compounds to be used in the Examples are
described as Reference Examples.
REFERENCE EXAMPLE 1
A 1.00 g portion of bicyclo[3.3.1]nonan-9-one and 1.35 g of
(3S)-(-)-3-(tert-butoxycarbonylamino)pyrrolidine were dissolved in
50 ml of methanol, and the solution was mixed with 0.10 g of 10%
palladium-carbon powder to carry out 2 hours of catalytic reduction
at room temperature in an atmosphere of hydrogen. The reaction
solution was filtered, and the resulting filtrate was concentrated
under a reduced pressure and then purified by column chromatography
(chloroform:methanol=10:1) to give 2.34 g of an intermediate, i.e.,
(3S)-1-(bicyclo[3.3.1]non-9-yl)-3-(tert-butoxycarbonylamino)pyrrolidine,
in the form of a oily material. This was dissolved in 4N
hydrochloric acid-ethyl acetate solution, followed by stirring for
30 minutes. A 30 ml portion of ether was added to the resulting
reaction solution, and the thus formed crystals were collected by
filtration and dried under a reduced pressure to give 1.80 g of
(3S)-3-amino-1-(bicyclo[3.3.1.]non-9-yl)pyrrolidine dihydrochloride
as white crystals.
Mass spectrometry data (m/z) FAB-MS: 209 (M.sup.+ +1) Nuclear
magnetic resonance spectrum (DMSO-d.sub.6, TMS internal standard)
.delta.: 1.49-1.58 (4H, m), 1.72-1.84 (6H, m), 2.55 (1H, m),
3.17-3.22 (2H, m), 3.31 (1H, m), 3.51-3.64 (2H, m), 3.74-3.87 (1H,
m), 4.02-4.10 (1H, m), 8.80 (2H, brs), 10.28 (1H, brs), 10.73 (1H,
brs)
REFERENCE EXAMPLE 2
A 2.00 g portion of 2-methoxy-4-methylbenzoic acid was dissolved in
10 ml of sulfuric acid. With stirring at 0.degree. C., 0.88 ml of
concentrated nitric acid was added thereto dropwise. After 4 hours
of stirring at room temperature, and ice water was added. The thus
formed crystals were collected by filtration, dried under a reduced
pressure and then purified by column chromatography
(chloroform:methanol=30:1) to give 1.32 g of
2-methoxy-4-methyl-5-nitrobenzoic acid as yellow crystals.
Mass spectrometry data (m/z) EI-MS: 211 (M.sup.+) Nuclear magnetic
resonance spectrum (CDCl.sub.3, TMS internal standard) .delta.:
2.72 (3H, s), 4.13 (3H, s), 6.95 (1H, s), 8.83 (1H, s)
REFERENCE EXAMPLE 3
In a stream of argon, 3.08 g of 4-amino-5-chloro-2-methoxybenzoic
acid and 1.00 g of cyclohexanone were added to 30 ml of acetic acid
at room temperature, 4.30 g of sodium triacetoxyborohydride was
added in small portions to the above solution, and then the
resulting mixture was stirred for 1 hour. After completion of the
reaction, the solvent was evaporated and the resulting residue was
mixed with water, extracted with chloroform and then washed with
saturated brine. After drying over anhydrous sodium sulfate, the
solvent was evaporated under a reduced pressure and the resulting
residue was purified by silica gel column chromatography
(chloroform:methanol=100:1-50:1) to give 0.37 g of
5-chloro-4-cyclohexylamino-2-methoxybenzoic acid.
Mass spectrometry data (m/z) FAB-MS: 284 (M.sup.+ +1) Nuclear
magnetic resonance spectrum (CDCl.sub.3, TMS internal standard)
.delta.: 1.00-2.30 (10H, m), 3.15-3.60 (1H, m), 4.03 (3H, s),
4.70-5.00 (1H, m), 6.14 (1H, s), 8.03 (1H, s), 9.80-10.80 (1H,
brs)
REFERENCE EXAMPLE 4
In the similar manner as described in Reference Example 3, 0.56 g
of 5-chloro-2-methoxy-4-propylaminobenzoic acid was obtained from
0.36 ml of propanal.
Mass spectrometry data (m/z) FAB-MS: 244 (M.sup.+ +1) Nuclear
magnetic resonance spectrum (DMSO-d.sub.6, TMS internal standard)
.delta.: 0.92 (3H, t, J=7.5 Hz), 1.58-1.64 (2H, m), 3.21 (2H, m),
3.81 (3H, s), 6.01 (1H, t, J=5.5 Hz), 6.24 (1H, s), 7.62 (1H, s),
11.87 (1H, brs)
REFERENCE EXAMPLE 5
In the same manner as described in Reference Example 3, 0.61 g of
5-chloro-4-cyclopropylmethylamino-2-methoxybenzoic acid was
obtained from 0.37 ml of cyclopropylaldehyde.
Mass spectrometry data (m/z) FAB-MS: 256 (M.sup.+ +1) Nuclear
magnetic resonance spectrum (DMSO-d.sub.6, TMS internal standard)
.delta.: 0.26-0.29 (2H, m), 0.46-0.51 (2H, m), 1.07-1.90 (1H, m),
3.12-3.15 (2H, m), 3.82 (3H, s), 6.00 (1H, t, J=5.5 Hz), 6.31 (1H,
s), 7.63 (1H, s), 11.86 (1H, s)
REFERENCE EXAMPLE 6
In the similar manner as described in Reference Example 3, 0.61 g
of 5-chloro-2-methoxy-4-neopentylaminobenzoic acid was obtained
from 0.98 ml of pivalaldehyde.
Mass spectrometry data (m/z) FAB-MS: 272 (M.sup.+ +1) Nuclear
magnetic resonance spectrum (DMSO-d.sub.6, TMS internal standard)
.delta.: 0.95 (9H, s), 3.10-3.12 (2H, m), 3.81 (3H, s), 5.57 (1H,
t, J=6.5 Hz), 6.37 (1H, s), 7.63 (1H, s), 11.87 (1H, s)
REFERENCE EXAMPLE 7
(1) In a stream of argon, 1.50 g of 4-chloro-2-methoxybenzoic acid
was added to 10 ml of sulfuric acid under ice-cooling, and 0.85 g
of potassium nitrate was added to the solution in small portions,
followed by 2 hours of stirring. After completion of the reaction,
the reaction solution was poured on crushed ice, and the thus
precipitated product of interest was collected by filtration,
washed with methanol and then dried under a reduced pressure to
give 1.74 g of 4-chloro-2-methoxy-5-nitrobenzoic acid.
Mass spectrometry data (m/z) EI-MS: 231 (M.sup.+) Nuclear magnetic
resonance spectrum (DMSO-d.sub.6, TMS internal standard) .delta.:
3.98 (3H, s), 7.50 (1H, s), 8.40 (1H, s), 12.50-13.50 (1H, brs)
(2) In a stream of argon, 0.45 g of sodium methanethiolate was
added to 5 ml of dimethyl sulfoxide at room temperature, and 0.50 g
of 4-chloro-5-nitro-2-methoxybenzoic acid was added in small
portions, followed by 2 hours of stirring. After completion of the
reaction, the reaction solution was poured into 1N hydrochloric
acid aqueous solution, and the thus precipitated product of
interest was collected by filtration, washed with water and then
dried under a reduced pressure to give 0.45 g of
2-methoxy-4-methylthio-5-nitrobenzoic acid.
Mass spectrometry data (m/z) EI-MS: 243 (M.sup.+) Nuclear magnetic
resonance spectrum (DMSO-d.sub.6, TMS internal standard) .delta.:
2.63 (3H, s), 4.05 (3H, s), 6.97 (1H, s), 8.60 (1H, s), 12.60-13.50
(1H, brs)
REFERENCE EXAMPLE 8
In a stream of argon, 0.30 g of metallic sodium was added to 5 ml
of methanol under ice-cooling, the mixture was stirred at room
temperature for a while and then 1.00 g of
4-chloro-2-methoxy-5-nitrobenzoic acid was added to the resulting
solution in small portions, followed by stirring at 80.degree. C.
for 8 hours. After completion of the reaction, the reaction
solution was poured into 1N hydrochloric acid aqueous solution, and
the thus precipitated product of interest was collected by
filtration, washed with water and then dried under a reduced
pressure to give 0.80 g of 2,4-dimethoxy-5-nitrobenzoic acid.
Mass spectrometry data (m/z) EI-MS: 227 (M.sup.+) Nuclear magnetic
resonance spectrum (DMSO-d.sub.6, TMS internal standard) .delta.:
4.00 (3H, s), 4.05 (3H, s), 6.88 (1H, s), 8.38 (1H, s), 12.70-13.30
(1H, brs)
(Alternative method) A 2.00 g portion of 2,4-dimethoxybenzoic acid
was dissolved in 30 ml of sulfuric acid, and 0.49 ml of
concentrated nitric acid was added under ice-cooling. After 3 hours
of stirring at room temperature, this was poured into 100 g of ice
water, and the thus formed crystals were collected by filtration,
washed with water-methanol and then dried under a reduced pressure
to give 1.41 g of 2,4-dimethoxy-5-nitrobenzoic acid. The
physicochemical properties were identical to those of the compound
obtained by the former method.
REFERENCE EXAMPLE 9
A 0.50 g portion of 2-methoxy-4-methylthio-5-nitrobenzoic acid was
suspended in 5 ml of acetic acid, and 0.77 ml of 30% hydrogen
peroxide aqueous solution was added thereto, followed by 12 hours
of stirring. After completion of the reaction, the reaction
solution was poured on crushed ice, and the thus precipitated
product of interest was collected by filtration, washed with water
and then dried under a reduced pressure to give 0.35 g of
4-methylsulfinyl-2-methoxy-5-nitrobenzoic acid.
Mass spectrometry data (m/z) EI-MS: 259 (M.sup.+) Nuclear magnetic
resonance spectrum (DMSO-d.sub.6, TMS internal standard) .delta.:
2.91 (3H, s), 4.08 (3H, s), 7.78 (1H, s), 8.55 (1H, s)
REFERENCE EXAMPLE 10
A 1.00 g portion of 4-chloro-2-methoxy-5-nitrobenzoic acid and 0.52
g of sodium hydroxide were dissolved in 20 ml of 40% methylamine
methanol solution, followed by stirring at room temperature for 12
hours. After completion of the reaction, the reaction solution was
poured on crushed ice and adjusted to pH 4 with 6N hydrochloric
acid aqueous solution. The thus precipitated product of interest
was collected by filtration, washed with water and dried under a
reduced pressure and then the resulting crude product was purified
by silica gel column chromatography (chloroform:methanol=20:1) to
give 0.30 g of 2-methoxy-4-methylamino-5-nitrobenzoic acid.
Mass spectrometry data (m/z) EI-MS: 226 (M.sup.+) Nuclear magnetic
resonance spectrum (DMSO-d.sub.6, TMS internal standard) .delta.:
3.02 (3H, d, J=4.5 Hz), 3.91 (3H, s), 6.24 (1H, s), 8.52 (1H,
s)
REFERENCE EXAMPLE 11
In a stream of argon, 0.49 ml of 1-propanol was added to 5 ml of
dimethylformamide, and 0.24 g of sodium hydride was added, followed
by a short period of stirring at room temperature. To the resulting
solution was added 0.50 g of 4-chloro-2-methoxy-5-nitrobenzoic acid
in small portions, followed by 2 hours of stirring. After
completion of the reaction, the reaction solution was poured into
1N hydrochloric acid aqueous solution, the thus precipitated
product of interest was collected by filtration, washed with water
and dried under a reduced pressure. The resulting crude product was
purified by silica gel column chromatography
(chloroform:methanol=100:1-10:1) to give 0.07 g of
2,4-dipropoxy-5-nitrobenzoic acid.
Mass spectrometry data (m/z) EI-MS: 283 (M.sup.+) Nuclear magnetic
resonance spectrum (DMSO-d.sub.6, TMS internal standard) .delta.:
0.98-1.04 (6H, m), 1.73-1.82 (4H, m), 4.16 (2H, t, J=6.5 Hz), 4.23
(2H, t, J=6.5 Hz), 6.84 (1H, s), 8.35 (1H, s), 12.80 (1H, brs)
REFERENCE EXAMPLE 12
(1) A 7.00 g portion of 2,4-dimethoxy-5-nitrobenzoic acid was
dissolved in 2-butanone, and 9.90 g of potassium carbonate and 3.6
ml of dimethyl sulfate were added, followed by 3 hours of heating
under reflux. After completion of the reaction, the reaction
solution was poured into 1N hydrochloric acid aqueous solution, and
the thus precipitated product of interest was collected by
filtration, washed with water and then dried under a reduced
pressure to give 5.45 g of methyl
2,4-dimethoxy-5-nitrobenzoate.
Mass spectrometry data (m/z) EI-MS: 241 (M.sup.+) Nuclear magnetic
resonance spectrum (DMSO-d.sub.6, TMS internal standard) .delta.:
3.79 (3H, s), 4.00 (3H, s), 4.06 (3H, s), 6.90 (1H, s), 8.38 (1H,
s)
(2) A 4.00 g portion of methyl 2,4-dimethoxy-5-nitrobenzoate was
dissolved in 200 ml of tetrahydrofuran, and 0.40 g of 10%
palladium-carbon was added, followed by stirring for 12 hours at
room temperature under normal pressure in an atmosphere of
hydrogen. After removing insoluble matter by filtration, the
solvent was evaporated under a reduced pressure to give 3.6 g of
methyl 5-amino-2,4-dimethoxybenzoate.
Mass spectrometry data (m/z) EI-MS: 211 (M.sup.+) Nuclear magnetic
resonance spectrum (DMSO-d.sub.6, TMS internal standard) .delta.:
3.72 (3H, s), 3.75 (3H, s), 3.86 (3H, s), 4.47-4.49 (2H, brs), 6.62
(1H, s), 7.08 (1H, s)
(3) A 0.65 g portion of methyl 5-amino-2,4-dimethoxybenzoate was
dissolved in a mixture solvent of 1.5 ml of water and 10 ml of
acetone, and 1.3 ml of concentrated hydrochloric acid was added
thereto, followed by dropwise addition of 0.23 g of sodium nitrite
dissolved in 1 ml of water under ice-cooling and subsequent
stirring for a while. Next, 0.35 g of cuprous chloride was added
and the mixture was warmed up to room temperature. After completion
of the reaction, insoluble matter was filtered and the resulting
residue was mixed with water, extracted with ethyl acetate and then
washed with water and saturated brine. After drying over anhydrous
sodium sulfate, the solvent was evaporated under a reduced pressure
and the resulting residue was purified by silica gel column
chromatography (chloroform:methanol=500:1-40:1) to give 0.56 g of
methyl 5-chloro-2,4-dimethoxybenzoate.
Mass spectrometry data (m/z) EI-MS: 230 (M.sup.+) Nuclear magnetic
resonance spectrum (DMSO-d.sub.6, TMS internal standard) .delta.:
3.75 (3H, s), 3.89 (3H, s), 3.97 (3H, s), 6.83 (1H, s), 7.72 (1H,
s)
(4) A 0.56 g portion of methyl 5-chloro-2,4-dimethoxybenzoate was
dissolved in 5 ml of tetrahydrofuran, and 10 ml of 2N sodium
hydroxide aqueous solution was added, followed by 4 hours of
heating under reflux. After completion of the reaction, the
reaction solution was poured into 1N hydrochloric acid aqueous
solution, and the thus precipitated product of interest was
collected by filtration, washed with water and then dried under a
reduced pressure to give 0.45 g of 5-chloro-2,4-dimethoxybenzoic
acid.
Mass spectrometry data (m/z) EI-MS: 216 (M.sup.+) Nuclear magnetic
resonance spectrum (DMSO-d.sub.6, TMS internal standard) .delta.:
3.89 (3H, s), 3.96 (3H, s), 6.82 (1H, s), 7.71 (1H, s), 12.40-12.60
(1H, brs)
REFERENCE EXAMPLE 13
(1) A 1.50 g portion of methyl 2,4-dihydroxybenzoate was dissolved
in 30 ml of acetone, and 3.10 g of potassium carbonate and 1.7 ml
of isopropyl iodide were added, followed by 48 hours of heating
under reflux. After completion of the reaction, the reaction
solution was poured into 1N hydrochloric acid aqueous solution,
extracted with chloroform and dried over anhydrous sodium sulfate
and then the solvent was evaporated under a reduced pressure. The
resulting residue was purified by silica gel column chromatography
(hexane:ethyl acetate=10:1-2:1) to give 1.60 g of methyl
2-hydroxy-4-isopropoxybenzoate.
Mass spectrometry data (m/z) EI-MS: 210 (M.sup.+) Nuclear magnetic
resonance spectrum (CDCl.sub.3, TMS internal standard) .delta.:
1.42 (6H, d, J=7.0 Hz), 3.90 (3H, s), 4.43-4.72 (1H, m), 6.31-6.44
(2H, m), 7.65-7.77 (1H, m), 10.91 (1H, s)
(2) A 1.60 g portion of methyl 2-hydroxy-4-isopropoxybenzoate was
dissolved in 30 ml of 2-butanone, 1.60 g of potassium carbonate and
1.1 ml of dimethyl sulfate were added, followed by 12 hours of
heating under reflux. After completion of the reaction, the solvent
was evaporated, the resulting residue was suspended in chloroform,
insoluble matter was removed by filtration through celite, and the
solvent was again evaporated. The resulting residue was purified by
silica gel column chromatography (hexane:ethyl acetate=10:1-2:1) to
give 1.70 g of methyl 4-isopropoxy-2-methoxybenzoate.
Mass spectrometry data (m/z) EI-MS: 224 (M.sup.+) Nuclear magnetic
resonance spectrum (CDCl.sub.3, TMS internal standard) .delta.:
1.36 (6H, d, J=6.0 Hz), 3.85 (3H, s), 3.87 (3H, s), 4.46-4.76 (1H,
m), 6.38-6.54 (2H, m), 7.76-7.88 (1H, m)
(3) A 3.20 g portion of methyl 4-isopropoxy-2-methoxybenzoate was
dissolved in 20 ml of tetrahydrofuran, and 30 ml of 2N sodium
hydroxide aqueous solution was added, followed by 2 hours of
heating under reflux. After completion of the reaction, the
reaction solution was poured into 1N hydrochloric acid aqueous
solution, extracted with chloroform and dried over anhydrous sodium
sulfate. Then, the solvent was evaporated under a reduced pressure
to give 2.60 g of 4-isopropoxy-2-methoxybenzoic acid.
Mass spectrometry data (m/z) EI-MS: 210 (M.sup.+) Nuclear magnetic
resonance spectrum (DMSO-d.sub.6, TMS internal standard) .delta.:
1.27 (6H, d, J=6.0 Hz), 3.78 (3H, s), 4.50-4.90 (1H, m), 6.48-6.58
(2H, m), 7.62-7.73 (1H, m), 12.00-12.20 (1H, brs)
(4) A 1.61 g portion of 4-isopropoxy-2-methoxybenzoic acid was
dissolved in 20 ml of acetic anhydride, 0.38 ml of concentrated
nitric acid and a small amount of acetic acid were added, followed
by stirring at room temperature for 2 hours. After completion of
the reaction, the reaction solution was poured on crushed ice,
extracted with chloroform and then dried over anhydrous sodium
sulfate. After evaporation of the solvent under a reduced pressure,
the resulting residue was dissolved in 5 ml of tetrahydrofuran and
5 ml of 1N sodium hydroxide aqueous solution, followed by stirring
for 1 hour. The reaction solution was poured into 1N hydrochloric
acid aqueous solution, extracted with chloroform and dried over
anhydrous sodium sulfate. The solvent was evaporated under a
reduced pressure and the resulting residue was purified by silica
gel column chromatography (chloroform:methanol=100:1-10:1) to give
0.43 g of 4-isopropoxy-2-methoxy-5-nitrobenzoic acid.
Mass spectrometry data (m/z) EI-MS: 255 (M.sup.+) Nuclear magnetic
resonance spectrum (DMSO-d.sub.6, TMS internal standard) .delta.:
1.35 (6H, d, J=6.0 Hz), 3.96 (3H, s), 4.80-5.20 (1H, m), 6.87 (1H,
s), 8.29 (1H, s)
REFERENCE EXAMPLE 14
(1) In the similar manner as described in Reference Example 13 (1),
1.50 g of methyl 2-hydroxy-4-propoxybenzoate was obtained from 1.7
ml of propyl iodide.
Mass spectrometry data (m/z) EI-MS: 210 (M.sup.+) Nuclear magnetic
resonance spectrum (CDCl.sub.3, TMS internal standard) .delta.:
1.03 (3H, t, J=7.0 Hz), 1.77-1.84 (2H, m), 3.91 (3H, s), 3.91-3.96
(2H, m), 6.40-6.44 (2H, m), 7.70-7.74 (1H, m), 10.93 (1H, s)
(2) In the similar manner as described in Reference Example 13 (2),
1.60 g of methyl 2-methoxy-4-propoxybenzoate was obtained from 1.50
g of methyl 2-hydroxy-4-propoxybenzoate.
Mass spectrometry data (m/z) EI-MS: 224 (M.sup.+) Nuclear magnetic
resonance spectrum (CDCl.sub.3, TMS internal standard) .delta.:
1.05 (3H, t, J=7.5 Hz), 1.65-1.94 (2H, m), 3.81 (3H, s), 3.85 (3H,
s), 3.81-4.04 (2H, m), 6.40-6.54 (2Hm)7.77-7.89 (1H, m)
(3) In the similar manner as described in Reference Example 13 (3),
1.40 g of 2-methoxy-4-propoxybenzoic acid was obtained from 1.60 g
of methyl 2-methoxy-4-propoxybenzoate.
Mass spectrometry data (m/z) EI-MS: 210 (M.sup.+) Nuclear magnetic
resonance spectrum (DMSO-d.sub.6, TMS internal standard) .delta.:
0.98 (3H, t, J=7.5 Hz), 1.68-1.79 (2H, m), 3.81 (3H, s), 4.00 (2H,
t, J=7.0 Hz), 6.53-6.61 (2H, m), 7.69 (2H, d, J=8.5 Hz), 12.11 (1H,
s)
(4) In the similar manner as described in Reference Example 13 (4),
3.20 g of 2-methoxy-5-nitro-4-propoxybenzoic acid was obtained from
3.00 g of 2-methoxy-4-propoxybenzoic acid.
Mass spectrometry data (m/z) EI-MS: 255 (M.sup.+) Nuclear magnetic
resonance spectrum (DMSO-d.sub.6, TMS internal standard) .delta.:
1.02 (3H, t, J=7.5 Hz), 1.76-1.82 (2H, m), 3.97 (3H, s), 4.25 (2H,
t, J=6.0 Hz), 6.86 (1H, s), 8.36 (1H, s), 12.83-12.92 (1H, brs)
REFERENCE EXAMPLE 15
(1) A 1.00 g portion of methyl 5-amino-2,4-dimethoxybenzoate was
dissolved in 5 ml of water, 0.50 ml of concentrated sulfuric acid
was added and then 356 mg of sodium nitrite dissolved in 2 ml of
water was added dropwise under ice-cooling, followed by a short
period of stirring. Separately, 1.00 g of cuprous cyanide was
dissolved in 4 ml of water and, with ice-cooling, 2.00 g of sodium
cyanide dissolved in 4 ml of water was added dropwise thereto,
followed by 1 hour of stirring. This was mixed with the previously
prepared solution and heated at 80.degree. C. to effect the
reaction, the resulting reaction solution was mixed with water,
extracted with chloroform and dried over anhydrous sodium sulfate.
The solvent was evaporated under a reduced pressure and then the
resulting residue was purified by silica gel column chromatography
(hexane:ethyl acetate=6:1 to chloroform:methanol=50:1) to give 0.65
g of methyl 5-cyano-2,4-dimethoxybenzoate.
Mass spectrometry data (m/z) EI-MS: 221 (M.sup.+) Nuclear magnetic
resonance spectrum (DMSO-d.sub.6, TMS internal standard) .delta.:
3.77 (3H, s), 3.97 (3H, s), 4.03 (3H, s), 6.86 (1H, s), 8.02 (1H,
s)
(2) A 0.80 g portion of methyl 5-cyano-2,4-dimethoxybenzoate was
dissolved in 8 ml of acetonitrile and 5 ml of water, and 7 ml of 2N
sodium hydroxide aqueous solution was added, followed by stirring
at room temperature for 6 hours. After completion of the reaction,
the reaction solution was poured into 2N hydrochloric acid aqueous
solution, extracted with chloroform and dried over anhydrous sodium
sulfate. The solvent was evaporated under a reduced pressure to
give 0.65 g of 5-cyano-2,4-dimethoxybenzoic acid.
Mass spectrometry data (m/z) EI-MS: 207 (M.sup.+) Nuclear magnetic
resonance spectrum (DMSO-d.sub.6, TMS internal standard) .delta.:
3.96 (3H, s), 4.02 (3H, s), 6.84 (1H, s), 8.00 (1H, s), 12.73 (1H,
s)
REFERENCE EXAMPLE 16
(1) In the similar manner as described in Reference Example 13 (1),
3.00 g of methyl 4-cyclopropylmethyloxy-2-hydroxybenzoate was
obtained from 5.00 g of cyclopropylmethyl bromide.
Mass spectrometry data (m/z) EI-MS: 222 (M.sup.+) Nuclear magnetic
resonance spectrum (CDCl.sub.3, TMS internal standard) .delta.:
0.32-0.40 (2H, m), 0.59-0.80 (2H, m), 1.10-1.54 (1H, m), 3.77-3.91
(2H, m), 3.91 (3H, s), 6.40-6.49 (2H, m), 7.66-7.79 (1H, m), 10.93
(1H, s)
(2) A 3.00 g portion of methyl
4-cyclopropylmethyloxy-2-hydroxybenzoate was dissolved in 70 ml of
2-butanone, and 2.80 g of potassium carbonate and 1.9 ml of
dimethyl sulfate were added, followed by 12 hours of heating under
reflux. After completion of the reaction, the solvent was
evaporated, the resulting residue was suspended in chloroform, and
insoluble matter was removed by celite filtration. The solvent was
again evaporated, and then the thus obtained residue was dissolved
in 20 ml of tetrahydrofuran, mixed with 30 ml of 2N sodium
hydroxide aqueous solution and subjected to 3 hours of heating
under reflux. After completion of the reaction, the reaction
solution was poured into 1N hydrochloric acid aqueous solution, and
the thus precipitated product of interest was collected by
filtration, washed with water and then dried under a reduced
pressure to give 2.74 g of 4-cyclopropylmethyloxy-2-methoxybenzoic
acid.
Mass spectrometry data (m/z) EI-MS: 222 (M.sup.+) Nuclear magnetic
resonance spectrum (DMSO-d.sub.6, TMS internal standard) .delta.:
0.30-0.36 (2H, m), 0.55-0.61 (2H, m), 1.21-1.25 (1H, m), 3.80 (3H,
s), 3.89 (2H, d, J=7.0 Hz), 6.54 (1H, dd, J=2.0, 8.5 Hz), 6.61 (1H,
d, J=2.0 Hz), 7.68 (1H, d, J=8.5 Hz), 12.10 (1H, s)
(3) In the similar manner as described in Reference Example 13 (4),
3.00 g of 4-cyclopropylmethyloxy-2-methoxy-5-nitrobenzoic acid was
obtained from 2.65 g of 4-cyclopropylmethyloxy-2-methoxybenzoic
acid.
Mass spectrometry data (m/z) EI-MS: 267 (M.sup.+) Nuclear magnetic
resonance spectrum (DMSO-d.sub.6, TMS internal standard) 0.37-0.42
(2H, m), 0.60-0.65 (2H, m), 1.26-1.31 (1H, m), 3.96 (3H, s), 4.17
(2H, d, J=6.5 Hz), 6.83 (1H, s), 8.35 (1H, s), 12.83-12.87 (1H,
s)
REFERENCE EXAMPLE 17
(1) In the similar manner as described in Reference Example 13 (1),
2.74 g of methyl 4-benzyloxy-2-hydroxybenzoate was obtained from
3.2 ml of benzyl bromide.
Mass spectrometry data (m/z) EI-MS: 258 (M.sup.+) Nuclear magnetic
resonance spectrum (CDCl.sub.3, TMS internal standard) .delta.:
3.90 (3H, s), 5.07 (2H, s), 6.48-6.54 (2H, m), 7.32-7.43 (5H, m),
7.74 (1H, d, J=8.75 Hz), 10.96 (1H, s)
(2) In the similar manner as described in Reference Example 16 (2),
2.66 g of 4-benzyloxy-2-methoxybenzoic acid was obtained from 2.74
g of methyl 4-benzyloxy-2-hydroxybenzoate.
Mass spectrometry data (m/z) EI-MS: 258 (M.sup.+) Nuclear magnetic
resonance spectrum (CDCl.sub.3, TMS internal standard) .delta.:
4.02 (3H, s), 5.13 (2H, s), 6.62 (1H, d, J=2.5 Hz), 6.73 (1H, dd,
J=8.75, 2.5 Hz), 7.33-7.44 (5H, m), 8.14 (1H, d, J=8.75 Hz),
10.45-10.49 (1H, brs)
(3) In the similar manner as described in Reference Example 13 (4),
0.45 g of 4-benzyloxy-2-methoxy-5-nitrobenzoic acid was obtained
from 1.00 g of 4-benzyloxy-2-methoxybenzoic acid.
Mass spectrometry data (m/z) EI-MS: 303 (M.sup.+) Nuclear magnetic
resonance spectrum (DMSO-d.sub.6, TMS internal standard) .delta.:
3.98 (3H, s), 5.46 (2H, s), 7.02 (1H, s), 7.34-7.55 (5H, m), 8.39
(1H, s), 12.90 (1H, s)
REFERENCE EXAMPLE 18
(1) A 3.00 g portion of methyl 2,4-dihydroxybenzoate was dissolved
in 30 ml of tetrahydrofuran, and 2 ml of cyclohexanol, 9.00 g of
triphenylphosphine and 7.38 ml of diisopropyl azodicarboxylate were
added, followed by stirring for 12 hours at room temperature. After
completion of the reaction, the solvent was evaporated, the
resulting residue was mixed with hexane-ethyl acetate, and
insoluble matter was removed by filtration. Solvent of the filtrate
was evaporated and the resulting residue was purified by silica gel
column chromatography (hexane:ethyl acetate=12:1-2:1) to give 1.70
g of methyl 4-cyclohexyloxy-2-hydroxybenzoate. Nuclear magnetic
resonance spectrum (DMSO-d.sub.6, TMS internal standard) .delta.:
1.10-2.10 (10H, m), 3.86 (3H, s), 4.40-4.48 (1H, m), 6.43-6.58 (2H,
m), 7.63-7.75 (1H, m), 10.71 (1H, s)
(2) In the similar manner as described in Reference Example 16 (2),
1.70 g of 4-cyclohexyloxy-2-methoxybenzoic acid was obtained from
1.70 g of methyl 4-cyclohexyloxy-2-hydroxybenzoate.
Mass spectrometry data (m/z) EI-MS: 250 (M.sup.+) Nuclear magnetic
resonance spectrum (CDCl.sub.3, TMS internal standard) .delta.:
1.28-1.44 (3H, m), 1.53-1.63 (3H, m), 1.80-1.88 (2H, m), 1.98-2.05
(2H, m), 4.02 (3H, s), 4.32-4.39 (1H, m), 6.52 (1H, d, J=2.0 Hz),
6.61 (1H, dd, J=2.0, 9.0 Hz), 8.06 (1H, d, J=9.0 Hz)
(3) In the similar manner as described in Reference Example 13 (4),
1.48 g of 4-cyclohexyloxy-2-methoxy-5-nitrobenzoic acid was
obtained from 1.60 g of 4-cyclohexyloxy-2-methoxybenzoic acid.
Mass spectrometry data (m/z) EI-MS: 295 (M.sup.+) Nuclear magnetic
resonance spectrum (DMSO-d.sub.6, TMS internal standard) .delta.:
1.27-1.90 (10H, m), 3.96 (3H, s), 4.87-4.93 (1H, m), 6.88 (1H, s),
8.33 (1H, s), 12.81-12.85 (1H, brs)
REFERENCE EXAMPLE 19
(1) A 1.00 g portion of norcamphor and 1.60 g of
(3S)-3-(tert-butoxycarbonylamino)pyrrolidine were dissolved in 20
ml of methanol, and 0.20 g of 10% palladium-carbon powder was
added, followed by stirring at room temperature for 12 hours in an
atmosphere of hydrogen. The reaction solution was filtered, the
thus obtained filtrate was concentrated under a reduced pressure.
Then, the resulting residue was purified by silica gel column
chromatography (chloroform:methanol=100:1-18:1) to give 2.27 g of
(3S)-3-(tert-butoxycarbonylamino)-1-(8,9,10-trinorborn-2-yl)pyrrolidine.
Mass spectrometry data (m/z) EI-MS: 280 (M.sup.+) Nuclear magnetic
resonance spectrum (DMSO-d.sub.6, TMS internal standard) .delta.:
0.80-0.83 (1H, m), 1.12-1.28 (3H, m), 1.28-1.36 (2H, m), 1.37 (9H,
s), 1.38-1.75 (3H, m), 1.76-1.80 (1H, m), 1.90-2.05 (1H, m),
2.05-2.25 (2H, m), 2.28-2.50 (2H, m), 2.60-2.70 (1H, m), 3.25-3.40
(1H, m), 3.75-3.90 (1H, m), 6.87-6.91 (1H, m)
(2) A 2.27 g portion of
(3S)-3-(tert-butoxycarbonylamino)-1-(8,9,10-trinorborn-2-yl)pyrrolidine
was dissolved in 20 ml of 4N hydrochloric acid-ethyl acetate
solution, followed by 3 hours stirring. After evaporation of the
solvent, the thus obtained product of interest, i.e.,
(3S)-3-amino-1-(8,9,10-trinorborn-2-yl)pyrrolidine dihydrochloride,
was used in the next reaction without purification.
REFERENCE EXAMPLE 20
(1) In the similar manner as described in Reference Example 13 (3),
5-amino-2,4-dimethoxybenzoic acid was obtained from 0.50 g of
methyl 5-amino-2,4-dimethoxybenzoate.
Mass spectrometry data (m/z) EI-MS: 197 (M.sup.+) Nuclear magnetic
resonance spectrum (DMSO-d.sub.6, TMS internal standard) .delta.:
3.77 (3H, s), 3.85 (3H, s), 6.61 (1H, s), 7.09 (1H, s)
REFERENCE EXAMPLE 21
(1) A 0.65 g portion of methyl 5-amino-2,4-dimethoxybenzoate was
dissolved in 10 ml of acetone and 1.5 ml of water, 1.80 ml of 48%
hydrobromic acid was added, and then 0.23 g of sodium nitrite
dissolved in 1 ml of water was added dropwise under ice-cooling,
followed by a short period of stirring. Next, 0.51 g of cuprous
bromide was added, and the mixture was warmed to room temperature.
After completion of the reaction, insoluble matter was filtered,
and the resulting residue was mixed with water, extracted with
chloroform and then dried over anhydrous sodium sulfate. By
evaporating the solvent under a reduced pressure, methyl
5-bromo-2,4-dimethoxybenzoate was obtained.
Mass spectrometry data (m/z) EI-MS: 276 (M.sup.+) Nuclear magnetic
resonance spectrum (DMSO-d.sub.6, TMS internal standard) .delta.:
3.75 (3H, s), 3.89 (3H, s), 3.96 (3H, s), 6.81 (1H, s), 7.86 (1H,
s)
(2) In the similar manner as described in Reference Example 13 (3),
0.45 g of 5-bromo-2,4-dimethoxybenzoic acid was obtained from
methyl 5-bromo-2,4-dimethoxybenzoate.
Mass spectrometry data (m/z) EI-MS: 260 (M.sup.+) Nuclear magnetic
resonance spectrum (DMSO-d.sub.6, TMS internal standard) .delta.:
3.89 (3H, s), 3.96 (3H, s), 6.79 (1H, s), 7.86 (1H, s), 12.49 (1H,
brs)
REFERENCE EXAMPLE 22
(1) In the similar manner as described in Reference Example 13 (4),
3.62 g of methyl 2-methoxy-5-nitro-4-propoxybenzoate was obtained
from methyl 2-methoxy-4-propoxybenzoate.
Mass spectrometry data (m/z) EI-MS: 269 (M.sup.+) Nuclear magnetic
resonance spectrum (DMSO-d.sub.6, TMS internal standard) .delta.:
1.02 (3H, t, J=7.5 Hz), 1.74-1.85 (2H, m), 3.79 (3H, s), 3.98 (3H,
s), 4.26 (2H, t, J=6.0 Hz), 6.88 (1H, s), 8.37 (1H, s)
(2) In the similar manner as described in Reference Example 12 (2),
2.90 g of methyl 5-amino-2-methoxy-4-propoxybenzoate was obtained
from 3.20 g of methyl 2-methoxy-5-nitro-4-propoxybenzoate.
Mass spectrometry data (m/z) EI-MS: 239 (M.sup.+) Nuclear magnetic
resonance spectrum (DMSO-d.sub.6, TMS internal standard) .delta.:
1.00 (3H, t, J=7.5 Hz), 1.72-1.82 (2H, m), 3.71 (3H, s), 3.73 (3H,
s), 4.01 (2H, t, J=6.5 Hz), 4.43-4.45 (1H, brs), 6.59 (1H, s), 7.07
(1H, s)
(3) In the similar manner as described in Reference Example 15 (1),
1.96 g of methyl 5-cyano-2-methoxy-4-propoxybenzoate was obtained
from 2.90 g of methyl 5-amino-2-methoxy-4-propoxybenzoate.
Mass spectrometry data (m/z) EI-MS: 249 (M.sup.+) Nuclear magnetic
resonance spectrum (DMSO-d.sub.6, TMS internal standard) .delta.:
1.02 (3H, t, J=7.5 Hz), 1.75-1.84 (2H, m), 3.76 (3H, s), 3.95 (3H,
s), 4.22 (2H, t, J=6.5 Hz), 6.85 (1H, s), 8.02 (1H, s)
(4) In the similar manner as described in Reference Example 15 (2),
1.55 g of 5-cyano-2-methoxy-4-propoxybenzoic acid was obtained from
1.96 g of methyl 5-cyano-2-methoxy-4-propoxybenzoate.
Mass spectrometry data (m/z) EI-MS: 235 (M.sup.+) Nuclear magnetic
resonance spectrum (DMSO-d.sub.6, TMS internal standard) .delta.:
1.02 (3H, t, J=7.5 Hz), 1.74-1.83 (2H, m), 3.94 (3H, s), 4.21 (2H,
t, J=6.5 Hz), 6.82 (1H, s), 7.99 (1H, s), 12.71 (1H, brs)
REFERENCE EXAMPLE 23
(1) In the similar manner as described in Reference Example 19 (1),
1.90 g of
(3S)-1-(2-adamantyl)-3-(tert-butoxycarbonylamino)pyrrolidine was
obtained from 0.85 g of 2-adamantanone.
Mass spectrometry data (m/z) EI-MS: 320 (M.sup.+) Nuclear magnetic
resonance spectrum (CDCl.sub.3, TMS internal standard) .delta.:
1.45 (9H, s), 1.55-1.63 (2H, m), 1.66-1.72 (5H, m), 1.75-1.85 (4H,
m), 1.85-1.97 (2H, m), 2.00-2.15 (3H, m), 2.15-2.30 (2H, m),
2.55-2.60 (2H, m), 2.76-2.90 (1H, m), 4.05-4.12 (1H, m), 4.80-4.90
(1H, m)
(2) In the similar manner as described in Reference Example 19 (2),
1.29 g of (3S)-1-(2-adamantyl)-3-aminopyrrolidine dihydrochloride
was obtained from 1.90 g of
(3S)-1-(2-adamantyl)-3-(tert-butoxycarbonylamino)pyrrolidine.
Mass spectrometry data (m/z) EI-MS: 220 (M.sup.+) Nuclear magnetic
resonance spectrum (DMSO-d.sub.6, TMS internal standard) .delta.:
1.60-1.75 (2H, m), 1.75-1.87 (4H, m), 1.80-2.00 (4H, m), 2.12-2.30
(2H, m), 2.30-2.58 (4H, m), 2.70-3.00 (1H, m), 3.22-3.45 (1H, m),
3.47-3.89 (2H, m), 3.89-4.11 (1H, m), 4.12-4.20 (1H, m), 9.02 (3H,
brs), 10.40-10.90 (1H, brm)
REFERENCE EXAMPLE 24
(1) Under ice-cooling, 1.00 g of 2,4-dimethoxybenzoic acid was
gradually added to 2 ml of chlorosulfonic acid, followed by
stirring at room temperature for 12 hours. The reaction solution
was poured on crushed ice, and the thus precipitated product of
interest was collected by filtration, washed with water and then
dried under a reduced pressure to give 1.03 g of
5-chlorosulfonyl-2,4-dimethoxybenzoic acid.
Mass spectrometry data (m/z) EI-MS: 280 (M.sup.+) Nuclear magnetic
resonance spectrum (DMSO-d.sub.6, TMS internal standard) .delta.:
3.87 (3H, s), 3.88 (3H, s), 6.62 (1H, s), 8.14 (1H, s), 13.74-13.84
(1H, brs)
(2) A 1.00 g portion of 5-chlorosulfonyl-2,4-dimethoxybenzoic acid
was added to 5 ml of saturated aqueous ammonia, followed by
stirring at room temperature for 1 hour. Then, 6N hydrochloric acid
aqueous solution was added to the reaction solution, and the thus
precipitated product of interest was collected by filtration,
washed with water and then dried under a reduced pressure to give
0.81 g of 5-aminosulfonyl-2,4-dimethoxybenzoic acid.
Mass spectrometry data (m/z) EI-MS: 261 (M.sup.+) Nuclear magnetic
resonance spectrum (DMSO-d.sub.6, TMS internal standard) .delta.:
3.94 (3H, s), 4.00 (3H, s), 6.80 (1H, s), 7.04 (2H, s), 8.15 (1H,
s), 12.20-12.80 (1H, brs)
REFERENCE EXAMPLE 25
(1) A 1.96 g portion of acetic anhydride was mixed with 0.89 ml of
formic acid, followed by stirring at 50.degree. C. for 2 hours. The
resulting solution was mixed with 1.5 g of methyl
5-amino-2,4-dimethoxybenzoate dissolved in advance in 3 ml of
tetrahydrofuran, followed by 6 hours stirring. After completion of
the reaction, the thus precipitated product of interest was
collected by filtration, washed with diethyl ether and then dried
under a reduced pressure to give 1.62 g of methyl
2,4-dimethoxy-5-formylaminobenzoate.
Mass spectrometry data (m/z) EI-MS: 239 (M.sup.+) Nuclear magnetic
resonance spectrum (DMSO-d.sub.6, TMS internal standard) .delta.:
3.74 (3H, s), 3.86 (3H, s), 3.95 (3H, s), 6.78 (1H, s), 8.24 (1H,
d, J=1.5 Hz), 8.50 (1H, s), 9.57-9.59 (1H, brm)
(2) A 1.60 g portion of methyl 2,4-dimethoxy-5-formylaminobenzoate
was dissolved in 20 ml of tetrahydrofuran, and 1.7 ml of borane
dimethylsulfide complex was added under ice-cooling, followed by 2
hours of stirring at 60.degree. C. Then, 3 ml of methanol and 4 ml
of concentrated hydrochloric acid were added, followed by stirring
at 75.degree. C. for a while and then spontaneously cooled. The
thus precipitated product of interest was collected by filtration,
washed with tetrahydrofuran and then dried under a reduced pressure
to give 1.08 g of methyl 2,4-dimethoxy-5-methylaminobenzoate.
Mass spectrometry data (m/z) EI-MS: 225 (M.sup.+) Nuclear magnetic
resonance spectrum (DMSO-d.sub.6, TMS internal standard) .delta.:
2.81 (3H, s), 3.77 (3H, s), 3.91 (3H, s), 4.02 (3H, s), 6.90 (1H,
s), 7.88 (1H, s), 10.40-11.00 (1H, brs)
(3) In the similar manner as described in Reference Example 13 (3),
2,4-dimethoxy-5-methylaminobenzoic acid was obtained from 1.08 g of
methyl 2,4-dimethoxy-5-methylaminobenzoate, which was used in the
next reaction without purification.
REFERENCE EXAMPLE 26
(1) To 20 g of crushed ice were added 3.7 ml of concentrated
sulfuric acid and 1.90 g of 5-chlorosulfonyl-2,4-dimethoxybenzoic
acid. Under ice-cooling, 2.40 g of zinc powder was added, and the
mixture was then heated under reflux. After completion of the
reaction, the reaction solution was diluted with ethyl acetate and
insoluble matter was removed by celite filtration. The thus
obtained filtrate was extracted with ethyl acetate, washed with
water and saturated brine and then dried over anhydrous sodium
sulfate. The solvent was evaporated under a reduced pressure and
the resulting residue was washed with diethyl ether to give 0.74 g
of 2,4-dimethoxy-5-mercaptobenzoic acid.
Mass spectrometry data (m/z) EI-MS: 214 (M.sup.+) Nuclear magnetic
resonance spectrum (CDCl.sub.3, TMS internal standard) .delta.:
3.62 (1H, s), 3.99 (3H, s), 4.07 (3H, s), 6.50 (1H, s), 8.07 (1H,
s), 10.15-10.70 (1H, brs)
(2) A 0.74 g portion of 2,4-dimethoxy-5-mercaptobenzoic acid was
dissolved in 10 ml of dimethylformamide, and 0.56 g of potassium
carbonate and 0.24 ml of methyl iodide were added, followed by
stirring at room temperature for 12 hours. After completion of the
reaction, the reaction solution was poured into 1N hydrochloric
acid aqueous solution, and the thus precipitated product of
interest was collected by filtration, washed with water and then
dried under a reduced pressure to give 0.46 g of
2,4-dimethoxy-5-methylthiobenzoic acid.
Mass spectrometry data (m/z) EI-MS: 228 (M.sup.+) Nuclear magnetic
resonance spectrum (DMSO-d.sub.6, TMS internal standard) .delta.:
2.49 (3H, s), 4.02 (3H, s), 4.07 (3H, s), 6.87 (1H, s), 7.70 (1H,
s), 12.36-12.40 (1H, brs)
REFERENCE EXAMPLE 27
In the similar manner as described in Reference Example 9, 0.91 g
of 2,4-dimethoxy-5-methylsulfinylbenzoic acid was obtained from
1.10 g of 2,4-dimethoxy-5-methylthiobenzoic acid.
Mass spectrometry data (m/z) EI-MS: 244 (M.sup.+) Nuclear magnetic
resonance spectrum (DMSO-d.sub.6, TMS internal standard) .delta.:
2.68 (3H, s), 3.93 (3H, s), 3.97 (3H, s), 6.81 (1H, s), 8.00 (1H,
s), 12.43 (1H, brs)
REFERENCE EXAMPLE 28
A 0.90 g portion of sodium sulfite and 1.81 g of sodium bicarbonate
were dissolved in 6 ml of water, and 2.00 g of
5-chlorosulfonyl-2,4-dimethoxybenzoic acid was added thereto,
followed by 1 hour stirring. Next, 1.50 g of bromoacetic acid was
added, followed by stirring at 75.degree. C. After completion of
the reaction, the reaction solution was poured into cool water, and
the thus precipitated product of interest was collected by
filtration, washed with water and then dried under a reduced
pressure to give 2,4-dimethoxy-5-methylsulfonylbenzoic acid, which
was used in the next reaction without purification.
REFERENCE EXAMPLE 29
(1) A 1.00 g portion of methyl 2,4-dimethoxybenzoate was suspended
in 0.58 ml of acetic acid, and 1.44 ml of dry trifluoroacetic acid
anhydride was added under ice-cooling, followed by stirring at room
temperature for 12 hours. Under ice-cooling, a saturated sodium
bicarbonate aqueous solution and ethyl acetate were added, and then
insoluble matter was removed by celite filtration. The thus
obtained filtrate was extracted with ethyl acetate, washed with
water and saturated brine and then dried over anhydrous sodium
sulfate. The solvent was evaporated under a reduced pressure, and
the resulting residue was purified by silica gel column
chromatography (chloroform:methanol=100:1-80:1) to give 0.99 g of
methyl 5-acetyl-2,4-dimethoxybenzoate.
Mass spectrometry data (m/z) EI-MS: 238 (M.sup.+) Nuclear magnetic
resonance spectrum (CDCl.sub.3, TMS internal standard) .delta.:
2.57 (3H, s), 3.86 (3H, s), 3.98 (3H, s), 3.98 (3H, s), 6.47 (1H,
s), 8.41 (1H, s)
(2) In the similar manner as described in Reference Example 15 (2),
0.75 g of 5-acetyl-2,4-dimethoxybenzoic acid was obtained from 0.99
g of methyl 5-acetyl-2,4-dimethoxybenzoate.
Mass spectrometry data (m/z) EI-MS: 224 (M.sup.+) Nuclear magnetic
resonance spectrum (DMSO-d.sub.6, TMS internal standard) .delta.:
2.52 (3H, s), 3.95 (3H, s), 4.01 (3H, s), 6.75 (1H, s), 8.15 (1H,
s), 12.20-13.70 (1H, brs)
REFERENCE EXAMPLE 30
(1) A 1.00 g portion of methyl 5-acetyl-2,4-dimethoxybenzoate was
dissolved in 10 ml of methanol, and 0.24 g of sodium borohydride
was added in small portions. After 10 minutes of stirring at room
temperature, 1N hydrochloric acid aqueous solution was added
thereto, and the thus precipitated product of interest was
collected by filtration, washed with water and then dried under a
reduced pressure to give 0.90 g of methyl
2,4-dimethoxy-5-(1-hydroxy)ethylbenzoate.
Mass spectrometry data (m/z) FAB-MS: 241 (M.sup.+ +1) Nuclear
magnetic resonance spectrum (CDCl.sub.3, TMS internal standard)
.delta.: 1.49 (3H, d, J=6.5 Hz), 2.32 (1H, d, J=5.0 Hz), 3.86 (3H,
s), 3.92 (3H, s), 3.93 (3H, s), 5.03-5.08 (1H, m), 6.46 (1H, s),
7.90 (1H, s)
(2) In the similar manner as described in Reference Example 15 (2),
0.77 g of 2,4-dimethoxy-5-(1-hydroxy)ethylbenzoic acid was obtained
from 0.89 g of methyl 2,4-dimethoxy-5-(1-hydroxy)ethylbenzoate.
Mass spectrometry data (m/z) EI-MS: 226 (M.sup.+) Nuclear magnetic
resonance spectrum (DMSO-d.sub.6, TMS internal standard) .delta.:
1.23 (3H, d, J=6.0 Hz), 3.85 (3H, s), 3.88 (3H, s), 4.70-5.20 (2H,
m), 6.63 (1H, s), 7.85 (1H, s), 11.80-12.20 (H, brs)
REFERENCE EXAMPLE 31
(1) A 0.50 g portion of methyl 5-acetyl-2,4-dimethoxybenzoate was
dissolved in 10 ml of trifluoroacetic acid, 0.83 ml of
triethylsilane was added, followed by 20 minutes stirring. After
evaporation of the solvent, the resulting residue was purified by
silica gel column chromatography (hexane:ethyl acetate=3:1) to give
0.50 g of methyl 2,4-dimethoxy-5-ethylbenzoate.
Mass spectrometry data (m/z) EI-MS: 224 (M.sup.+) Nuclear magnetic
resonance spectrum (CDCl.sub.3, TMS internal standard) .delta.:
1.16 (3H, d, J=7.5 Hz), 2.57 (2H, q, J=7.5 Hz), 3.86 (3H, s), 3.88
(3H, s), 3.91 (3H, s), 6.44 (1H, s), 7.67 (1H, s)
(2) In the similar manner as described in Reference Example 15 (2),
0.55 g of 2,4-dimethoxy-5-ethylbenzoic acid was obtained from 0.60
g of methyl 2,4-dimethoxy-5-ethylbenzoate.
Mass spectrometry data (m/z) EI-MS: 210 (M.sup.+) Nuclear magnetic
resonance spectrum (CDCl.sub.3, TMS internal standard) .delta.:
1.17 (3H, d, J=7.5 Hz), 2.59 (2H, q, J=7.5 Hz), 3.91 (3H, s), 4.08
(3H, s), 6.47 (1H, s), 7.95 (1H, s), 10.55 (1H, brs)
REFERENCE EXAMPLE 32
A 0.44 g portion of sodium hydride (50% oily form) was washed with
n-hexane and dissolved in 50 ml of dimethyl sulfoxide, and 1.64 ml
of propanethiol was added dropwise. After 15 minutes of stirring at
room temperature, 2.00 g of 4-chloro-2-methoxy-5-nitrobenzoic acid
which has been dissolved in 20 ml of dimethyl sulfoxide was added
dropwise, followed by 3 hours of stirring at room temperature.
Then, 50 ml of water was added to the reaction solution, and the
thus formed crystals were collected by filtration. The crystals
were suspended in 50 ml of methanol, and 10 ml of 1 N hydrochloric
acid was added, followed by stirring. The crystals were collected
by filtration and then dried under a reduced pressure to give 0.82
g of 2-methoxy-5-nitro-4-propylthiobenzoic acid.
Mass spectrometry data (m/z) FAB-MS: 257 (M.sup.- -1) Nuclear
magnetic resonance spectrum (DMSO-d.sub.6, TMS internal standard)
.delta.: 1.06 (3H, t), 1.74 (2H, q), 3.14 (2H, t), 4.02 (3H, s),
7.00 (1H, s), 8.57 (1H, s), 13.15 (1H, br)
REFERENCE EXAMPLE 33
A 10 ml portion of 40% methylamine methanol solution was mixed with
500 mg of 5-nitro-4-chloro-O-anisic acid and sealed in a tube to
carry out 24 hours of stirring at 50.degree. C. The reaction
solution was poured into ice water and adjusted to a pH value of
around 2 with 6N hydrochloric acid, and the thus formed precipitate
was collected by filtration. This was dried under a reduced
pressure to give 420 mg of 2,4-bis(methylamino)-5-chlorobenzoic
acid.
Mass spectrometry data (m/z) EI-MS: 255 (EI, M.sup.+) Nuclear
magnetic resonance spectrum (DMSO-d.sub.6, TMS internal standard)
.delta.: 2.90 (3H, d, J=5.0 Hz), 2.94 (3H, d, J=5.0 Hz), 5.58 (1H,
s), 8.34-8.50 (2H, m), 8.65 (1H, s), 12.60-13.20 (1H, brs)
REFERENCE EXAMPLE 34
In an atmosphere of argon, 4.80 g of methyl
2-methoxy-4-propanoylaminobenzoate was dissolved in 50 ml of
tetrahydrofuran and, at room temperature, 1.9 ml (20.2 mmol) of
borane dimethylsulfide complex was added in small portions. After 1
hour of reflux, and excess reagent was decomposed with dilute
hydrochloric acid under ice-cooling. The reaction solution was
extracted with chloroform, the resulting organic layer was washed
with water and saturated brine, dried over anhydrous sodium sulfate
and concentrated under a reduced pressure. Then, the resulting
residue was purified by silica gel column chromatography
(chloroform:methanol=100:1) to give 3.19 g of methyl
2-methoxy-4-propylaminobenzoate. Next, in an atmosphere of argon,
this compound and 2.5 ml of pyridine were dissolved in 50 ml of
methylene chloride, and 2.1 ml of anhydrous trifluoroacetic acid
was slowly added dropwise under ice-cooling. After 12 hours of
stirring at room temperature, the reaction solution was poured in
ice water, stirred for a while and then extracted with methylene
chloride. The organic layer was washed with water and saturated
brine, dried over anhydrous sodium sulfate and concentrated under a
reduced pressure. Then, the resulting residue was purified by
silica gel column chromatography (chloroform:methanol=200:1) to
give 3.88 g of methyl
2-methoxy-4-(propyltrifluoroacetyl)aminobenzoate.
Mass spectrometry data (m/z) FAB-MS: 320 (M.sup.+ +1) Nuclear
magnetic resonance spectrum (CDCl.sub.3, TMS internal standard)
.delta.: 0.93 (3H, t, J=7.5 Hz), 1.58-1.66 (2H, m), 3.71 (2H, m),
3.90 (3H, s), 3.91 (3H, s), 6.80 (1H, m), 6.85 (1H, m), 7.84 (1H,
m)
REFERENCE EXAMPLE 35
A 3.70 g portion of methyl
2-methoxy-4-(propyltrifluoroacetyl)aminobenzoate was dissolved in
20 ml of concentrated sulfuric acid to which, and 1.29 g of
potassium nitrate was added in small portions under ice-cooling,
followed by 2 hours of stirring. The reaction solution was poured
into ice water and extracted with ethyl acetate, and the resulting
organic layer was washed with saturated sodium bicarbonate aqueous
solution, water and saturated brine, which was then dried over
anhydrous sodium sulfate. The solvent was evaporated under a
reduced pressure and the resulting residue was purified by silica
gel column chromatography (chloroform:methanol=100:1) to give 4.30
g of methyl
2-methoxy-5-nitro-4-(propyltrifluoroacetyl)aminobenzoate.
Mass spectrometry data (m/z) FAB-MS: 365 (FAB, M.sup.+ +1) Nuclear
magnetic resonance spectrum (CDCl.sub.3, TMS internal standard)
.delta.: 0.94 (3H, t, J=7.5 Hz), 1.56-1.66 (2H, m), 3.18 (1H, m),
3.96 (3H, s), 4.02 (3H, s), 4.16 (1H, m), 6.87 (1H, s), 8.72 (1H,
s)
REFERENCE EXAMPLE 36
A 4.30 g portion of methyl
2-methoxy-5-nitro-4-(propyltrifluoroacetyl)aminobenzoate was
dissolved in 10 ml of acetonitrile, and the solution was mixed with
15 ml of 2N sodium hydroxide, followed by stirring at 60.degree. C.
for 2 hours. The reaction solution was cooled to room temperature,
poured into ice water and adjusted to a pH value of around 4 using
concentrated hydrochloric acid, and the thus formed precipitate was
collected by filtration and dried at 50.degree. C. under a reduced
pressure to give 2.54 g of 2-methoxy-5-nitro-4-propylaminobenzoic
acid as yellow powdery crystals.
Mass spectrometry data (m/z) FAM-MS: 255 (M.sup.+ +1) Nuclear
magnetic resonance spectrum (CDCl.sub.3, TMS internal standard)
.delta.: 0.98 (3H, t, J=7.5 Hz), 1.66-1.73 (2H, m), 3.37-3.42 (2H,
m), 3.93 (3H, s), 6.33 (1H, s), 8.49 (1H, t, J=5.5 Hz), 8.58 (1H,
s), 12.49 (1H, brs)
REFERENCE EXAMPLE 37
A 2.0 g portion of
4-cyclopropylcarbonylamino-5-chloro-2-methoxybenzoic acid and 856
mg of potassium hydroxide were dissolved in 30 ml of methanol, and
600 mg of 10% palladium-carbon powder was added, followed by
stirring at room temperature for 9 hours in an atmosphere of
hydrogen. The reaction solution was filtered, and the filtrate was
concentrated under a reduced pressure, diluted with 1N hydrochloric
acid aqueous solution and then extracted with chloroform. The
organic layer was washed with water and saturated brine in that
order and dried over anhydrous sodium sulfate. Then, the solvent
was evaporated under a reduced pressure and the resulting residue
was washed with diethyl ether to give 1.60 g of
4-cyclopropylcarbonylamino-2-methoxybenzoic acid.
Mass spectrometry data (m/z) FAB-MS: 235 (M.sup.+ +1) Nuclear
magnetic resonance spectrum (DMSO-d.sub.6, TMS internal standard)
.delta.: 0.81-0.84 (4H, m), 1.80 (1H, m), 3.77 (3H, s), 7.14 (1H,
d, J=8.5 Hz), 7.52 (1H, s), 7.66 (1H, d, J=8.5 Hz), 10.44 (1H, s),
12.21 (1H, brs)
REFERENCE EXAMPLE 38
A 780 mg portion of 4-cyclopropylcarbonylamino-2-methoxybenzoic
acid was dissolved in 10 ml of acetic anhydride and 0.5 ml of
acetic acid, and 790 .mu.l of concentrated nitric acid was slowly
added to the above solution under ice-cooling, followed by 2 hours
of stirring. The reaction solution was poured into ice water, and
the thus formed precipitate was collected by filtration and dried
under a reduced pressure to give 713 mg of
4-cyclopropylcarbonylamino-2-methoxy-5-nitrobenzoic acid.
Mass spectrometry data (m/z) FAB-MS: 281 (M.sup.+ +1) Nuclear
magnetic resonance spectrum (DMSO-d.sub.6, TMS internal standard)
.delta.: 0.87-0.94 (4H, m), 1.95 (1H, m), 3.90 (3H, s), 7.86 (1H,
s), 8.41 (1H, s), 10.75 (1H, s), 12.80 (1H, brs)
EXAMPLE 1
A 0.37 g portion of 5-chloro-4-cyclohexylamino-2-methoxybenzoic
acid and 0.36 ml of triethylamine were added to 15 ml of methylene
chloride and, with stirring at -30.degree. C., 0.19 ml of ethyl
chloroformate was added dropwise thereto, followed by 30 minutes of
stirring at -30.degree. C. A 0.59 g portion of
(3S)-3-amino-1-(bicyclo[3.3.1]non-9-yl)pyrroridine dihydrochloride
which had been dissolved in 5 ml of methylene chloride and 0.58 ml
of triethylamine was added dropwise to the above reaction solution,
and the mixture was slowly warmed up to room temperature, stirred
for additional 3 hours and then mixed with 50 ml of saturated
brine. The organic layer was again washed twice with saturated
brine, dried over anhydrous sodium sulfate and then concentrated
under a reduced pressure to give a crude product. This was purified
by silica gel column chromatography
(chloroform:methanol=100:1-10:1), converted into hydrochloride
using a 4N hydrochloric acid-ethyl acetate solution and then
crystallized from ethyl acetate to give 0.10 g of
(S)-N-[1-(bicyclo[3.3.1]non-9-yl)-3-pyrroridinyl]-5-chloro-4-cyclohexylami
no-2-methoxybenzamide monohydrochloride.
EXAMPLE 2
To 10 ml of dimethylformamide, 0.30 g of
5-chloro-2-methoxy-4-propylaminobenzoic acid, 0.38 g of
(3S)-3-amino-1-(bicyclo[3.3.1]non-9-yl)pyrroridine dihydrochloride
and 0.56 ml of triethylamine were added under ice-cooling, and
further 0.29 ml of diphenylphosphoryl azide was added dropwise,
followed by warming to room temperature with stirring. Under
ice-cooling, the reaction solution was poured into ice water and
extracted with ethyl acetate, and the organic layer was washed with
water and saturated brine in that order and then dried over
anhydrous sodium sulfate. After evaporation of the solvent, the
resulting residue was purified by silica gel column chromatography
(chloroform:methanol=100:1-10:1), converted into hydrochloride
using a 4N hydrochloric acid-ethyl acetate solution and then
crystallized from ethyl acetate to give 0.15 g of
(S)-N-[1-(bicyclo[3.3.1]non-9-yl)-3-pyrroridinyl]-5-chloro-2-methoxy-4-pro
pylaminobenzamide monohydrochloride.
The following compounds of Examples 3 to 36 were synthesized using
the procedure of Example 1 or 2.
EXAMPLE 3
In the similar manner as described in Example 1, 0.16 g of
(S)-N-[1-(bicyclo[3.3.1]non-9-yl]-5-chloro-2-methoxy-4-methylaminobenzamid
e was obtained from 0.28 g of
5-chloro-2-methoxy-4-methylaminobenzoic acid.
EXAMPLE 4
In the similar manner as described in Example 2, 0.30 g of
(S)-N-[1-(bicyclo[3.3.1]non-9-yl)-3-pyrrolidinyl]-5-chloro-4-cyclopropylme
thylamino-2-methoxybenzamide monohydrochloride was obtained from
0.30 g of 5-chloro-4-cyclopropylmethylamino-2-methoxybenzoic
acid.
EXAMPLE 5
In the similar manner as described in Example 2, 0.28 g of
(S)-N-[1-(bicyclo[3.3.1]non-9-yl)-3-pyrrolidinyl]-5-chloro-2-methoxy-4-neo
pentylaminobenzamide monohydrochloride was obtained from 0.25 g of
5-chloro-2-methoxy-4-neopentylaminobenzoic acid.
EXAMPLE 6
In the similar manner as described in Example 2, 0.30 g of
(S)-N-[1-(bicyclo[3.3.1]non-9-yl)-3-pyrrolidinyl]-2-methoxy-4-methylthio-5
-nitrobenzamide was obtained from 0.45 g of
2-methoxy-4-methylthio-5-nitrobenzoic acid.
EXAMPLE 7
In the similar manner as described in Example 2, 0.48 g of
(S)-N-[1-(bicyclo[3.3.1]non-9-yl)-3-pyrrolidinyl]-2,4-dimethoxy-5-nitroben
zamide was obtained from 0.35 g of 2,4-dimethoxy-5-nitrobenzoic
acid.
EXAMPLE 8
In the similar manner as described in Example 2, 0.31 g of
(S)-N-[1-(bicyclo[3.3.1]non-9-yl)-3-pyrrolidinyl]-2-methoxy-4-methylsulfin
yl-5-nitrobenzamide was obtained from 0.30 g of
2-methoxy-4-methylsulfinyl-5-nitrobenzoic acid.
EXAMPLE 9
In the similar manner as described in Example 2, 0.20 g of
(S)-N-[1-(bicyclo[3.3.1]non-9-yl)-3-pyrrolidinyl]-2,4-dimethoxybenzamide
monohydrochloride was obtained from 0.25 g of 2,4-dimethoxybenzoic
acid.
EXAMPLE 10
In the similar manner as described in Example 2, 0.37 g of
(S)-N-[1-(bicyclo[3.3.1]non-9-yl)-3-pyrrolidinyl]-2,4,5-trimethoxybenzamid
e monohydrochloride was obtained from 0.29 g of
2,4,5-trimethoxybenzoic acid.
EXAMPLE 11
In the similar manner as described in Example 2, 0.46 g of
(S)-N-[1-(bicyclo[3.3.1]non-9-yl)-3-pyrrolidinyl]-2-methoxy-4-methylthiobe
nzamide monohydrochloride was obtained from 0.44 g of
2-methoxy-4-methylthiobenzoic acid.
EXAMPLE 12
In the similar manner as described in Example 2, 0.08 g of
(S)-N-[1-(bicyclo[3.3.1]non-9-yl)-3-pyrrolidinyl]-2-methoxy-4-methylamino-
5-nitrobenzamide was obtained from 0.28 g of
2-methoxy-4-methylamino-5-nitrobenzoic acid.
EXAMPLE 13
In the similar manner as described in Example 2, 0.08 g of
(S)-N-[1-(bicyclo[3.3.1]non-9-yl)-3-pyrrolidinyl]-2,4-dipropoxy-5-nitroben
zamide monohydrochloride was obtained from 0.07 g of
2,4-dipropoxy-5-nitrobenzoic acid.
EXAMPLE 14
In the similar manner as described in Example 2, 0.39 g of
(S)-N-[1-(bicyclo[3.3.1]non-9-yl)-3-pyrrolidinyl]-5-chloro-2,4-dimethoxybe
nzamide was obtained from 0.43 g of 5-chloro-2,4-dimethoxybenzoic
acid.
EXAMPLE 15
In the similar manner as described in Example 2, 0.35 g of
(S)-N-[1-(bicyclo[3.3.1]non-9-yl)-3-pyrrolidinyl]-2-methoxy-4-methylbenzam
ide monohydrochloride was obtained from 0.34 g of
2-methoxy-4-methylbenzoic acid.
EXAMPLE 16
In the similar manner as described in Example 2, 0.55 g of
(S)-N-[1-(bicyclo[3.3.1]non-9-yl)-3-pyrrolidinyl]-2-methoxy-4-methyl-5-nit
robenzamide was obtained from 0.43 g of
2-methoxy-4-methyl-5-nitrobenzoic acid.
EXAMPLE 17
In the similar manner as described in Example 2, 0.38 g of
(S)-N-[1-(bicyclo[3.3.1]non-9-yl)-3-pyrrolidinyl]-4-isopropoxy-2-methoxy-5
-nitrobenzamide monohydrochloride was obtained from 0.40 g of
4-isopropoxy-2-methoxy-5-nitrobenzoic acid.
EXAMPLE 18
In the similar manner as described in Example 2, 0.55 g of
(S)-N-[1-(bicyclo[3.3.1]non-9-yl)-3-pyrrolidinyl]-2-methoxy-5-nitro-4-prop
oxybenzamide monohydrochloride was obtained from 0.40 g of
2-methoxy-5-nitro-4-propoxybenzoic acid.
EXAMPLE 19
In the similar manner as described in Example 2, 0.12 g of
(S)-N-[1-(bicyclo[3.3.1]non-9-yl)-3-pyrrolidinyl]-5-cyano-2,4-dimethoxyben
zamide was obtained from 0.30 g of 5-cyano-2,4-dimethoxybenzoic
acid.
EXAMPLE 20
In the similar manner as described in Example 2, 0.43 g of
(S)-N-[1-(bicyclo[3.3.1]non-9-yl)-3-pyrrolidinyl]-4-cyclopropylmethyloxy-2
-methoxy-5-nitrobenzamide was obtained from 0.42 g of
4-cyclopropylmethyloxy-2-methoxy-5-nitrobenzoic acid.
EXAMPLE 21
In the similar manner as described in Example 2, 0.21 g of
(S)-4-benzyloxy-N-[1-(bicyclo[3.3.1]non-9-yl)-3-pyrrolidinyl]-2-methoxy-5-
nitrobenzamide was obtained from 0.23 g of
4-benzyloxy-2-methoxy-5-nitrobenzoic acid.
EXAMPLE 22
In the similar manner as described in Example 2, 0.25 g of
(S)-N-[1-(bicyclo[3.3.1]non-9-yl)-3-pyrrolidinyl]-4-cyclohexyloxy-2-methox
y-5-nitrobenzamide was obtained from 0.46 g of
4-cyclohexyloxy-2-methoxy-5-nitrobenzoic acid.
EXAMPLE 23
In the similar manner as described in Example 2, 0.22 g of
2-methoxy-5-nitro-4-propoxy-N-[(3S)-1-(8,9,10-trinorborn-2-yl)pyrrolidinyl
]benzamide was obtained from 0.40 g of
2-methoxy-5-nitro-4-propoxybenzoic acid and 0.42 g of
(3S)-3-amino-1-(8,9,10-trinorborn-2-yl)pyrrolidine
dihydrochloride.
EXAMPLE 24
In the similar manner as described in Example 2, 0.11 g of
(S)-5-amino-N-[1-(bicyclo[3.3.1]non-9-yl)-3-pyrrolidinyl]-2,4-dimethoxyben
zamide monofumarate was obtained from 5-amino-2,4-dimethoxybenzoic
acid.
EXAMPLE 25
In the similar manner as described in Example 2, 0.33 g of
(S)-N-[1-(bicyclo[3.3.1]non-9-yl)-3-pyrrolidinyl]-5-bromo-2,4-dimethoxyben
zamide was obtained from 0.41 g of 5-bromo-2,4-dimethoxybenzoic
acid.
EXAMPLE 26
In the similar manner as described in Example 2, 0.38 g of
(S)-N-[1-(bicyclo[3.3.1]non-9-yl)-3-pyrrolidinyl]-2-methoxy-5-nitro-4-prop
ylthiobenzamide was obtained from 0.40 g of
2-methoxy-5-nitro-4-propylthiobenzoic acid.
EXAMPLE 27
In the similar manner as described in Example 2, 0.07 g of
(S)-N-[1-(bicyclo[3.3.1]non-9-yl)-3-pyrrolidinyl]-5-cyano-2-methoxy-4-prop
oxybenzamide was obtained from 0.37 g of
5-cyano-2-methoxy-4-propoxybenzoic acid.
EXAMPLE 28
In the similar manner as described in Example 2, 0.52 g of
(S)-N-[1-(2-adamantyl)-3-pyrrolidinyl]-5-cyano-2-methoxy-4-propoxybenzamid
e was obtained from 0.37 g of 5-cyano-2-methoxy-4-propoxybenzoic
acid.
EXAMPLE 29
In the similar manner as described in Example 2, 0.22 g of
(S)-5-aminosulfonyl-N-[1-(bicyclo[3.3.1]non-9-yl)-3-pyrrolidinyl]-2,4-dime
thoxybenzamide was obtained from 0.39 g of
5-aminosulfonyl-2,4-dimethoxybenzoic acid.
EXAMPLE 30
In the similar manner as described in Example 2, 0.58 g of
(S)-N-[1-(bicyclo[3.3.1]non-9-yl)-3-pyrrolidinyl]-2,4-dimethoxy-5-methylam
inobenzamide hemifumarate was obtained from
2,4-dimethoxy-5-methylaminobenzoic acid.
EXAMPLE 31
In the similar manner as described in Example 2, 0.15 g of
(S)-N-[1-(bicyclo[3.3.1]non-9-yl)-3-pyrrolidinyl]-2,4-dimethoxy-5-methylth
iobenzamide was obtained from 0.21 g of
2,4-dimethoxy-5-methylthiobenzoic acid.
EXAMPLE 32
In the similar manner as described in Example 2, 0.16 g of
(S)-N-[1-(bicyclo[3.3.1]non-9-yl)-3-pyrrolidinyl]-2,4-dimethoxy-5-methylsu
lfinylbenzamide was obtained from 0.40 g of
2,4-dimethoxy-5-methylsulfinylbenzoic acid.
EXAMPLE 33
In the similar manner as described in Example 2, 0.12 g of
(S)-N-[1-(bicyclo[3.3.1]non-9-yl)-3-pyrrolidinyl]-2,4-dimethoxy-5-methylsu
lfonylbenzamide was obtained from
2,4-dimethoxy-5-methylsulfonylbenzoic acid.
EXAMPLE 34
In the similar manner as described in Example 2, 0.37 g of
(S)-5-acetyl-N-[1-(bicyclo[3.3.1]non-9-yl)-3-pyrrolidinyl]-2,4-dimethoxybe
nzamide was obtained from 0.35 g of 5-acetyl-2,4-dimethoxybenzoic
acid.
EXAMPLE 35
In the similar manner as described in Example 2, 0.30 g of
(S)-N-[1-(bicyclo[3.3.1]non-9-yl)-3-pyrrolidinyl]-5-(1-hydroxyethyl)-2,4-d
imethoxybenzamide was obtained from 0.36 g of
2,4-dimethoxy-5-(1-hydroxy)ethylbenzoic acid.
EXAMPLE 36
In the similar manner as described in Example 2, 0.22 g of
(S)-N-[1-(bicyclo[3.3.1]non-9-yl)-3-pyrrolidinyl]-5-ethyl-2,4-dimethoxyben
zamide was obtained from 0.50 g of 2,4-dimethoxy-5-ethylbenzoic
acid.
EXAMPLE 37
In the similar manner as described in Example 2,
(S)-N-[1-(bicyclo[3.3.1]non-9-yl)-3-pyrrolidinyl]-2,4-bis(methylamino)-5-n
itrobenzamide was obtained from 2,4-bis(methylamino)-5-nitrobenzoic
acid and (3S)-3-amino-1-(bicyclo[3.3.1]non-9-yl)pyrrolidine
dihydrochloride.
EXAMPLE 38
A 647 mg portion of
(S)-5-amino-N-[1-(bicyclo[3.3.1]non-9-yl)-3-pyrrolidinyl]-2,4-dimethoxyben
zamide was dissolved in 6 ml of acetonitrile, and 1.35 ml of 37%
formalin aqueous solution, 315 mg of sodium cyanoborohydride and
0.1 ml of acetic acid were added under ice-cooling, followed by
stirring at room temperature for 7 hours. The reaction solution was
mixed with sodium bicarbonate aqueous solution and extracted with
chloroform, and the resulting organic layer was washed with water
and saturated brine. The solvent was evaporated under a reduced
pressure, and the resulting residue was purified by silica gel
column chromatography (chloroform-methanol=100:1-20:1) to give 572
mg of a yellow oily material. This was dissolved in ethanol and
mixed with 76 mg of fumaric acid, and the thus formed precipitate
was collected by filtration to give 313 mg of
(S)-N-[1-(bicyclo[3.3.1]non-9-yl)-3-pyrrolidinyl]-5-dimethylamino-2,4-dime
thoxybenzamide monofumarate.
EXAMPLE 39
In the similar manner as described in Example 2, 450 mg of
(S)-4-amino-N-[1-(bicyclo[3.3.1]non-9-yl)-3-pyrrolidinyl]-2-methoxy-5-nitr
obenzamide was synthesized from 400 mg of
4-amino-2-methoxy-5-nitrobenzoic acid and 624 mg of
(3S)-3-amino-1-(bicyclo[3.3.1]non-9-yl)pyrrolidine
dihydrochloride.
EXAMPLE 40
In the similar manner as described in Example 2, 622 mg of
(S)-N-[1-(bicyclo[3.3.1]non-9-yl)-3-pyrrolidinyl]-2-methoxy-5-nitro-4-prop
ylaminobenzamide was synthesized from 500 mg of
2-methoxy-5-nitro-4-propylaminobenzoic acid and 582 mg of
(3S)-3-amino-1-(bicyclo[3.3.1]non-9-yl)pyrrolidine.
dihydrochloride.
EXAMPLE 41
In the similar manner as described in Example 2, 276 mg of
(S)-N-[1-(bicyclo[3.3.1]non-9-yl)-3-pyrrolidinyl]-4-cyclopropylcarbonylami
no-2-methoxy-5-nitrobenzamide was synthesized from 321 mg of
4-cyclopropylcarbonylamino-2-methoxy-5-nitrobenzoic acid and 355 mg
of (3S)-3-amino-1-(bicyclo[3.3.1]non-9-yl)pyrrolidine
dihydrochloride.
Chemical structures and physicochemical properties of the compounds
obtained in the above Examples are shown in the following Table
4.
TABLE 4
__________________________________________________________________________
##STR71## Example No. R.sup.1 X R.sup.2 R.sup.3 R.sup.4
Physicochemical
__________________________________________________________________________
Properties 1 ##STR72## NH ##STR73## OCH.sub.3 Cl Melting point:
212-217.degree. C. lemental analysis: C.sub.27 H.sub.40 N.sub.3
O.sub.2 Cl.HCl -0.5H.sub.2 O C % H % N % Cl % Measured 62.42 8.15
8.09 13.65 Calcd. 62.43 8.05 8.30 13.80 Mass analysis: (m/z) 474
(FAB, M.sup.+ +1) 2 C.sub.3 H.sub.7 NH ##STR74## OCH.sub.3 Cl
Melting point: 195-203.degree. C. lemental analysis: C.sub.24
H.sub.36 N.sub.3 O.sub.2 Cl.HCl C % H % N % Cl % Measured 61.27
7.93 8.93 15.07 Calcd. 61.05 8.05 8.91 14.80 Mass analysis: (m/z)
434 (FAB, M.sup.+ +1) 3 CH.sub.3 NH ##STR75## OCH.sub.3 Cl Melting
point: 183-184.degree. C. lemental analysis: C.sub.22 H.sub.32
N.sub.3 O.sub.2 Cl C % H % N % Cl % Measured 65.09 7.94 10.35 8.73
Calcd. 64.96 7.99 10.34 8.91 Mass analysis: (m/z) 406 (FAB, M.sup.+
+1) 4 ##STR76## NH ##STR77## OCH.sub.3 Cl Melting point:
200-205.degree. C. lemental analysis: C.sub.25 H.sub.36 N.sub.3
O.sub.2 Cl.HCl -0.6H.sub.2 O C % H % N % Cl % Measured 60.87 7.81
8.52 14.37 Calcd. 60.72 7.59 8.56 14.35 Mass analysis: (m/z) 446
(FAB, M.sup.+ +1) 5 CH.sub.2 C(CH.sub.3).sub.3 NH ##STR78##
OCH.sub.3 Cl Melting point: 210-231.degree. C. lemental analysis:
C.sub.26 H.sub.40 N.sub.3 O.sub.2 Cl.HCl C % H % N % Cl % Measured
62.64 8.29 8.43 14.22 Calcd. 62.30 8.30 8.36 14.23 Mass analysis:
(m/z) 462 (FAB, M.sup.+ +1) 6 CH.sub.3 S ##STR79## OCH.sub.3
NO.sub.2 Melting point: 176-179.degree. C. lemental analysis:
C.sub.22 H.sub.31 N.sub.3 O.sub.4 S C % H % N % S % Measured 60.95
7.21 9.69 7.40 Calcd. 60.79 7.09 9.60 7.45 Mass analysis: (m/z) 434
(FAB, M.sup.+ +1) 7 CH.sub.3 O ##STR80## OCH.sub.3 NO.sub.2 Melting
point: 225-229.degree. C. lemental analysis: C.sub.22 H.sub.31
N.sub.3 O.sub.5.0.2H.sub. 2 O C % H % N % Measured 62.75 7.52 9.98
Calcd. 62.85 7.36 10.12 Mass analysis: (m/z) 418 (FAB, M.sup.+ +1)
8 CH.sub.3 SO ##STR81## OCH.sub.3 NO.sub.2 Melting point:
176-188.degree. C. lemental analysis: C.sub.22 H.sub.31 N.sub.3
O.sub.6 S C % H % N % S % Measured 58.78 6.95 9.35 7.13 Calcd.
58.50 6.95 9.26 6.84 Mass analysis: (m/z) 450 (FAB, M.sup.+ +1) 9
CH.sub.3 O ##STR82## OCH.sub.3 OCH.sub.3 Melting point:
214-217.degree. C. lemental analysis: C.sub.22 H.sub.32 N.sub.2
O.sub.3.HCl C % H % N % Cl % Measured 64.61 8.13 6.85 8.67 Calcd.
64.36 8.24 6.80 8.64 Mass analysis: (m/z) 373 (FAB, M.sup.+ +1) 10
CH.sub.3 O ##STR83## OCH.sub.3 OCH.sub.3 Melting point:
234-240.degree. C. lemental analysis: C.sub.22 H.sub.34 N.sub.2
O.sub.4.HCl -0.5H.sub.2 O C % H % N % Cl % Measured 61.66 8.10 6.25
7.91 Calcd. 61.59 8.00 6.14 7.99 Mass analysis: (m/z) 403 (FAB,
M.sup.+ +1) 11 CH.sub.3 S ##STR84## OCH.sub.3 H Melting point:
226-228.degree. C. lemental analysis: C.sub.22 H.sub.32 N.sub.2
O.sub.2 S.HCl -0.1H.sub.2 O C % H % N % S% Cl % Measured 61.91 7.84
6.56 7.51 8.31 Calcd. 61.86 7.73 6.59 7.45 8.36
Mass analysis: (m/z) 389 (FAB, M.sup.+ +1) 12 CH.sub.3 NH ##STR85##
OCH.sub.3 NO.sub.2 Melting point: 225-229.degree. C. lemental
analysis: C.sub.22 H.sub.32 N.sub.4 O.sub.4 C % H % N % Measured
63.44 7.74 13.45 Calcd. 63.19 7.84 13.26 Mass analysis: (m/z) 417
(FAB, M.sup.+ +1) 13 C.sub.3 H.sub.7 O ##STR86## OC.sub.3 H.sub.7
NO.sub.2 Melting point: 223-230.degree. C. lemental analysis:
C.sub.26 H.sub.39 N.sub.3 O.sub.5.HCl -0.2H.sub.2 O C % H % N % Cl
% Measured 60.79 7.93 8.18 6.90 Calcd. 60.79 7.91 8.13 6.83 Mass
analysis: (m/z) 474 (FAB, M.sup.+ +1) 14 CH.sub.3 O ##STR87##
OCH.sub.3 Cl Melting point: 165-169.degree. C. lemental analysis:
C.sub.22 H.sub.31 N.sub.2 O.sub.3 Cl C % H % N % Cl % Measured
64.93 7.68 6.88 8.71 Calcd. 64.83 7.59 6.87 8.72 Mass analysis:
(m/z) 407 (FAB, M.sup.+ +1) 15 CH.sub.3 Bond ##STR88## OCH.sub.3 H
Melting point: 244-246.degree. C. lemental analysis: C.sub.22
H.sub.32 N.sub.2 O.sub.2.HCl -0.3H.sub.2 O C % H % N % Cl %
Measured 66.33 8.50 7.03 8.90 Calcd. 66.30 8.43 7.02 8.76 Mass
analysis: (m/z) 357 (FAB, M.sup.+ +1) 16 CH.sub.3 Bond ##STR89##
OCH.sub.3 NO.sub.2 Melting point: 160-161.degree. C. lemental
analysis: C.sub.22 H.sub.31 N.sub.3 O.sub.4 C % H % N % Measured
65.81 7.78 10.47 Calcd. 65.71 7.77 10.48 Mass analysis: (m/z) 402
(FAB, M.sup.+ +1) 17 CH(CH.sub.3).sub.2 O ##STR90## OCH.sub.3
NO.sub.2 Melting point: 161-164.degree. C. lemental analysis:
C.sub.24 H.sub.35 N.sub.2 O.sub.5.HCl -H.sub.2 O C % H % N % Cl %
Measured 57.65 7.66 8.40 7.09 Calcd. 57.66 7.51 8.31 6.91 Mass
analysis: (m/z) 446 (FAB, M.sup.+ +1) 18 C.sub.3 H.sub.7 O
##STR91## OCH.sub.3 NO.sub.2 Melting point: 157-163.degree. C.
lemental analysis: C.sub.24 H.sub.35 N.sub.3 O.sub.5.HCl.0.8H.
sub.2 O C % H % N % Cl % Measured 58.07 7.63 8.46 7.14 Calcd. 57.91
7.52 8.46 7.20 Mass analysis: (m/z) 446 (FAB, M.sup.+ +1) 19
CH.sub.3 O ##STR92## OCH.sub.3 CN Melting point: 206-212.degree. C.
lemental analysis: C.sub.23 H.sub.31 N.sub.3 O.sub.3.0.2H.sub. 2 O
C % H % N % Measured 68.87 7.89 10.48 Calcd. 68.99 7.88 10.49 Mass
analysis: (m/z) 398 (FAB, M.sup.+ +1) 20 ##STR93## O ##STR94##
OCH.sub.3 NO.sub.2 Melting point: 167-170.degree. C. lemental
analysis: C.sub.25 H.sub.36 N.sub.3 O.sub.6.0.1H.sub. 2 O C % H % N
% Measured 65.37 7.72 9.15 Calcd. 65.27 7.73 9.16 Mass analysis:
(m/z) 458 (FAB, M.sup.+ +1) 21 ##STR95## O ##STR96## OCH.sub.3
NO.sub.2 Melting point: 174-178.degree. C. lemental analysis:
C.sub.23 H.sub.35 N.sub.3 O.sub.5 C % H % N % Measured 68.13 7.14
8.51 Calcd. 67.94 7.18 8.54 Mass analysis: (m/z) 494 (FAB, M.sup.+
+1) 22 ##STR97## O ##STR98## OCH.sub.3 NO.sub.2 Melting point:
87-92.degree. C. Elemental analysis: C.sub.27 H.sub.39 N.sub.3
O.sub.5.1.1H.sub. 2 O C % H % N % Measured 64.16 8.22 8.31 Calcd.
64.01 8.33 8.24 Mass analysis: (m/z) 486 (FAB, M.sup.+ +1) 23
C.sub.3 H.sub.7 O ##STR99## OCH.sub.3 NO.sub.2 Melting point:
120-123.degree. C. lemental analysis: C.sub.22 H.sub.31 N.sub.3
O.sub.5.0.2H.sub. 2 O C % H % N % Measured 62.75 7.52 9.98
Calcd. 62.63 7.56 10.00 Mass analysis: (m/z) 418 (FAB, M.sup.+ +1)
24 CH.sub.3 O ##STR100## OCH.sub.3 NH.sub.2 Melting point:
195-200.degree. C. lemental analysis: C.sub.22 H.sub.33 N.sub.3
O.sub.3.C.sub.4 H.sub.4 O.sub.4.0.5H.sub.2 O C % H % N % Measured
60.92 7.47 8.20 Calcd. 60.61 7.20 8.02 Mass analysis: (m/z) 388
(FAB, M.sup.+ +1) 25 CH.sub.3 O ##STR101## OCH.sub.3 Br Melting
point: 173-178.degree. C. .sub.22 H.sub.31 N.sub.2 O.sub.3 Br C % H
% N % Br % Measured 58.54 6.92 6.21 17.70 Calcd. 58.73 7.09 6.15
17.40 Mass analysis: (m/z) 451 (FAB, M.sup.+ +1) 26 C.sub.3 H.sub.7
S ##STR102## OCH.sub.3 NO.sub.2 Melting point: 129-130.degree. C.
lemental analysis: C.sub.24 H.sub.35 N.sub.3 O.sub.4 S C % H % N %
S % Measured 62.45 7.64 9.10 6.95 Calcd. 62.26 7.60 9.02 7.04 Mass
analysis: (m/z) 462 (FAB, M.sup.+ +1) 27 C.sub.3 H.sub.7 O
##STR103## OCH.sub.3 CN Melting point: 147-150.degree. C. lemental
analysis: C.sub.25 H.sub.35 N.sub.3 O.sub.3.0.2H.sub. 2 O C % H % N
% Measured 69.97 8.31 9.79 Calcd. 69.88 8.22 9.82 Mass analysis:
(m/z) 426 (FAB, M.sup.+ +1) 28 C.sub.3 H.sub.7 O ##STR104##
OCH.sub.3 CN Melting point: 172-177.degree. C. lemental analysis:
C.sub.26 H.sub.35 N.sub.3 O.sub.3.0.3H.sub. 2 O C % H % N %
Measured 70.50 8.10 9.49 Calcd. 70.58 7.97 9.55 Mass analysis:
(m/z) 438 (FAB, M.sup.+ +1) 29 CH.sub.3 O ##STR105## OCH.sub.3
SO.sub.2 NH.sub.2 Melting point: 245-250.degree. C. lemental
analysis: C.sub.22 H.sub.33 N.sub.3 O.sub.6 S.0.8H.su b.2 O C % H %
N % S % Measured 56.70 7.48 9.02 6.88 Calcd. 56.58 7.36 8.91 7.13
Mass analysis: (m/z) 452 (FAB, M.sup.+ +1) 30 CH.sub.3 O ##STR106##
OCH.sub.3 NHCH.sub.2 Melting point: amorphous Elemental analysis:
C.sub.23 H.sub.35 N.sub.3 O.sub.3.0.5C.sub.4 H.sub.4
O.sub.4.0.5H.sub.2 O C % H % N % Measured 64.08 8.17 8.97 Calcd.
63.85 8.27 8.64 Mass analysis: (m/z) 402 (FAB, M.sup.+ +1) 31
CH.sub.3 O ##STR107## OCH.sub.3 SCH.sub.3 Melting point:
120-123.degree. C. lemental analysis: C.sub.23 H.sub.34 N.sub.2
O.sub.3 S.0.4H.su b.2 O C % H % N % S % Measured 64.88 8.24 6.58
7.53 Calcd. 65.03 8.22 6.52 7.63 Mass analysis: (m/z) 419 (FAB,
M.sup.+ +1) 32 CH.sub.3 O ##STR108## OCH.sub.3 SOCH.sub.3 Melting
point: 213-220.degree. C. .sub.23 H.sub.34 N.sub.2 O.sub.4
S.0.7H.sub.2 O C % H % N % S % Measured 61.77 7.98 6.26 7.17 Calcd.
61.48 7.65 6.22 7.54 Mass analysis: (m/z) 435 (FAB, M.sup.+ +1) 33
CH.sub.3 O ##STR109## OCH.sub.3 SO.sub.2 CH.sub.3 Melting point:
197-201.degree. C. lemental analysis: C.sub.23 H.sub.34 N.sub.2
O.sub.5 S C % H % N % S % Measured 61.31 7.61 6.22 7.12 Calcd.
61.03 7.58 6.16 7.12 Mass analysis: (m/z) 451 (FAB, M.sup.+ +1) 34
CH.sub.3 O ##STR110## OCH.sub.3 COCH.sub.3 Melting point:
218-226.degree. C. lemental analysis: C.sub.24 H.sub.34 N.sub.2
O.sub.4 C % H % N % Measured 69.54 8.27 6.76 Calcd. 69.75 8.30 6.76
Mass analysis: (m/z) 415 (FAB, M.sup.+ +1) 35 CH.sub.3 O ##STR111##
OCH.sub.3 ##STR112## Melting point: 168-173.degree. C. lemental
analysis: C.sub.24 H.sub.36 N.sub.2 O.sub.4 C % H % N % Measured
69.20 8.71
6.72 Calcd. 69.30 8.76 6.71 Mass analysis: (m/z) 417 (FAB, M.sup.+
+1) 36 CH.sub.3 O ##STR113## OCH.sub.3 C.sub.2 H.sub.5 Melting
point: 133-135.degree. C. lemental analysis: C.sub.24 H.sub.36
N.sub.2 O.sub.3 C % H % N % Measured 71.96 9.06 6.99 Calcd. 71.90
9.12 6.93 Mass analysis: (m/z) 401 (FAB, M.sup.+ +1) 37 CH.sub.3 NH
##STR114## NHCH.sub.3 NO.sub.2 Melting point: 193-196.degree. C.
lemental analysis: C.sub.22 H.sub.33 N.sub.5 O.sub.3.0.4H.sub. 2 O
C % H % N % Measured 62.51 8.06 16.57 Calcd. 62.88 7.92 16.79 Mass
analysis: (m/z) 416 (FAB, M.sup.+ +1) 38 CH.sub.3 O ##STR115##
OCH.sub.3 N(CH.sub.3).sub.2 Melting point: 166-169.degree. C.
lemental analysis: C.sub.24 H.sub.37 N.sub.3 O.sub.3.C.sub.4
H.sub.4 O.sub.4.0.3H.sub.2 O C % H % N % Measured 62.62 7.81 7.82
Calcd. 62.58 7.76 7.81 Mass analysis: (m/z) 416 (FAB, M.sup.+ +1)
39 H NH ##STR116## OCH.sub.3 NO.sub.2 Melting point:
272-274.degree. C. lemental analysis: C.sub.21 H.sub.30 N.sub.4
O.sub.4.0.2H.sub. 2 O C % H % N % Measured 62.11 7.55 13.80 Calcd.
61.99 7.52 13.80 Mass analysis: (m/z) 403 (FAB, M.sup.+ +1) 40
C.sub.3 H.sub.7 NH ##STR117## OCH.sub.3 NO.sub.2 Melting point:
189-191.degree. C. lemental analysis: C.sub.24 H.sub.36 N.sub.4
O.sub.4 C % H % N % Measured 64.84 8.16 12.60
Calcd. 64.61 8.23 12.61 Mass analysis: (m/z) 445 (FAB, M.sup.+ +1)
41 ##STR118## CONH ##STR119## OCH.sub.3 NO.sub.2 Melting point:
189-191.degree. C. lemental analysis: C.sub.26 H.sub.34 N.sub.4
O.sub.5 C % H % N % Measured 63.81 7.28 11.91 Calcd. 63.54 7.26
11.79 Mass analysis: (m/z) 471 (FAB, M.sup.+ +1)
__________________________________________________________________________
Formulation Examples
The following illustrates Formulation Examples of the compound of
the present invention as pharmaceutical drugs.
______________________________________ 1) (mg)
______________________________________ Invention compound 10.0
Lactose 109.6 Microcrystalline cellulose 27.4 Light anhydrous
silicic acid 1.5 Magnesium stearate 1.5
______________________________________
Using a DC type mixer, 30 g of the compound of the present
invention was mixed with 328.8 g of lactose and 82.2 g of
microcrystalline cellulose. The mixture was applied to a roller
compactor to effect compression molding, thereby obtaining a flaky
compressed material. The flaky compressed material was pulverized
using a hammer mill, and the pulverized material was screened
through a 20 mesh screen. To the thus screened material were added
4.5 g of light anhydrous silicic acid and 4.5 g of magnesium
stearate, followed by mixing in the DC type mixer. The resulting
mixture was applied to a tablet making machine using a die-punch of
7.5 mm in diameter, thereby obtaining 3,000 tablets each having a
weight of 150 mg.
______________________________________ 2) (mg)
______________________________________ Invention compound 10.0
Lactose 91.7 Corn starch 39.3 Polyvinyl pyrrolidone K25 7.5
Magnesium stearate 1.5 Hydroxypropylmethylcellulose 2910 2.3
Polyethylene glycol 6000 0.4 Titaniuin dioxide 1.1 Purified talc
0.7 ______________________________________
A 30 g portion of the compound of the present invention was mixed
with 275.1 g of lactose and 117.9 g of corn starch in a fluidized
bed granulating machine. Separately, 22.5 g of polyvinyl
pyrrolidine was dissolved in 127.5 g of water to prepare a binding
solution. Using the fluidized bed granulating machine, the binding
solution was sprayed to the above mixture to give granules. A 4.5 g
portion of magnesium stearate was added to the thus obtained
granules, followed by mixing in the DC type mixer. The resulting
mixture was applied to a tablet making machine using a die-punch of
7.5 mm in diameter, thereby obtaining 3,000 tablets each having a
weight of 150 mg.
Separately, a coating liquid was prepared by suspending 2.3 g of
hydroxypropylmethylcellulose 2910, 0.4 g of polyethylene glycol
6000, 1.1 g of titanium dioxide and 0.7 g of purified talc in 24.2
g of water. Using a high coater, 3,000 tablets obtained above were
coated with the coating liquid to give film coated tablets each
having a weight of 154.5 mg.
* * * * *